Biotechnology Advances xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv Research review paper Medicinal plants used in the treatment of tuberculosis - Ethnobotanical and ethnopharmacological approaches Javad Sharifi-Rada,⁎, Bahare Salehib,⁎⁎, Zorica Z. Stojanović-Radićc, Patrick Valere Tsouh Fokoud,e, Marzieh Sharifi-Radf, Gail B. Mahadyg, Majid Sharifi-Radh, Mohammad-Reza Masjedii, Temitope O. Lawalg,j, Seyed Abdulmajid Ayatollahia,k, Javid Masjedii, Razieh Sharifi-Radl, William N. Setzerm, Mehdi Sharifi-Radn,⁎⁎⁎, Farzad Kobarfarda,o, Atta-ur Rahmanp, Muhammad Iqbal Choudharyp, Athar Ataq, Marcello Iritir,⁎⁎⁎⁎ a Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš, Višegradska 33, Niš, Serbia d Department of Clinical Pathology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra LG 581, Ghana e Antimicrobial Agents Unit, LPMPS, Department of Biochemistry, Faculty of Science, University of Yaoundé 1, Yaoundé 812, Cameroon f Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran g Department of Pharmacy Practice, Clinical Pharmacognosy Laboratories, University of Illinois at Chicago, USA h Department of Range and Watershed Management, Faculty of Natural Resources, University of Zabol, Zabol, Iran i Tobacco Control Strategic Research Center, Shahid Beheshti University of Medical Sciences Tehran, Iran j Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria k Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences Tehran, Iran l Department of Biology, Faculty of Science, University of Zabol, Zabol, Iran m Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA n Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran o Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Iran p H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan q Department of Chemistry, Richardson College for the Environmental Science Complex The University of Winnipeg, Winnipeg, Canada r Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan 20133, Italy b c A R TICL E INFO A BSTR A CT Keywords: Mycobacterium Multi drug-resistance Traditional healing systems Herbal medicine Antimycobacterial agents Evidence-based medicine Tuberculosis is a highly infectious disease declared a global health emergency by the World Health Organization, with approximately one third of the world's population being latently infected with Mycobacterium tuberculosis. Tuberculosis treatment consists in an intensive phase and a continuation phase. Unfortunately, the appearance of multi drug-resistant tuberculosis, mainly due to low adherence to prescribed therapies or inefficient healthcare structures, requires at least 20 months of treatment with second-line, more toxic and less efficient drugs, i.e., capreomycin, kanamycin, amikacin and fluoroquinolones. Therefore, there exists an urgent need for discovery and development of new drugs to reduce the global burden of this disease, including the multi-drug-resistant tuberculosis. To this end, many plant species, as well as marine organisms and fungi have been and continue to be used in various traditional healing systems around the world to treat tuberculosis, thus representing a nearly unlimited source of active ingredients. Besides their antimycobacterial activity, natural products can be useful in adjuvant therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their adverse effects and to reverse mycobacterial multi-drug resistance due to the genetic plasticity and environmental adaptability of Mycobacterium. However, even if some natural products have still been investigated in preclinical ⁎ Correspondence to: J. Javad Sharifi-Rad, Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Correspondence to: B. Salehi, Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. ⁎⁎⁎ Correspondence to: M. Sharifi-Rad, Department of Medical Parasitology, Zabol University of Medical Sciences, 61663335 Zabol, Iran. ⁎⁎⁎⁎ Correspondence to: M. Iriti, Department of Agricultural and Environmental Sciences, Milan State University, via G. Celoria 2, Milan 20133, Italy. E-mail addresses: javad.sharifirad@sbmu.ac.ir (J. Sharifi-Rad), bahar.salehi007@gmail.com (B. Salehi), mehdi_sharifirad@yahoo.com (M. Sharifi-Rad), marcello.iriti@unimi.it (M. Iriti). ⁎⁎ http://dx.doi.org/10.1016/j.biotechadv.2017.07.001 Received 29 December 2016; Received in revised form 22 June 2017; Accepted 5 July 2017 0734-9750/ © 2017 Elsevier Inc. All rights reserved. Please cite this article as: Sharifi-Rad, J., Biotechnology Advances, https://doi.org/10.1016/j.biotechadv.2017.07.001 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. and clinical studies, the validation of their efficacy and safety as antituberculosis agents is far from being reached, and, therefore, according to an evidence-based approach, more high-level randomized clinical trials are urgently needed. route of entrance of tubercle bacilli into the body is in form of aerosol droplets via the lung. As these microbes reach the alveoli, they face and are engulfed by alveolar macrophages, and may infect type II pneumocytes. Later, dendritic cells, T lymphocytes, cytokines and many other mediators and biologic factors interfere and appear in the scene and lead to the development of typical granulomatas and necrosis which we are not described in detail in this introduction (Mehta et al., 1996; Tascon et al., 2000). The main strategy of TB treatment was focused on DOT's strategy, that is “Directly Observed Treatment short course”, which is 6 months treatment. In the initial two months, the patient receives 4 major drugs (RIF, INH, pyrazinamide, ethambutol) under close observation by health worker or defined volunteer person, and the following 4 months will continue with two drugs (RIF and INH). This six month regimen is recommended to all cases of pulmonary and extra-pulmonary cases including children and older patients. As mentioned earlier, MDR TB which includes cases resistant to both RIF and INH, was reported in 1990 by WHO and is a real obstacle in the general control of this disease worldwide. In the year 2006, XDR types were reported and it seems that 3.2% of all new cases of TB and 20% of those who received treatment were MDR (Holtz and Cegielski, 2007; Chiang et al., 2010; Millard et al., 2015; Ghanashyam, 2016). In the year 2014, almost 190,000 patients with MDR had died and only 50% of those with MDR were treated successfully. With the introduction of linezolid (Farshidpour et al., 2013; Lee et al., 2015) in 2000, and bedaquiline (Diacon et al., 2009; WHO, 2013) in 2009, WHO recommended new therapeutic regimens to deal with MDR and XDR cases. A relevant issue in the field of tuberculosis is vaccine use. Historically, the extensively used vaccine worldwide is BCG (Bacillus Calmette-Guérin) vaccine. This vaccine, made from a weak strain of Mycobacterium bovis, was introduced 80 years ago and is still recommended by WHO to be used in early childhood as one of the 6 essential vaccines, particularly in prevalent areas. BCG vaccine is effective in preventing development of severe forms of TB in children, mainly biliary tuberculosis and meningitis. This vaccine is less effective in preventing tuberculous disease among adults (Bedi, 2005). Recent advances in the molecular biology and immunopathogenesis of mycobacterial diseases have led to extensive research in these fields and different vaccines have been introduced to be used as a preventive or therapeutic (Lalvani et al., 2013; Mangtani et al., 2014; Kaufmann et al., 2015). However, we should wait for affordable and effective vaccines in the coming years. The complex scenario is the interaction between the immune system and tubercle bacilli after the preliminary infection, which, in most cases, leads to latent tuberculosis infection (LTI). As mentioned earlier, in > 80% of cases, the human body is able to contain the infection and the bacilli remain dormant through the whole life of infected people. This phenomenon is a subject of extensive research (Parrish et al., 1998; Wayne and Sohaskey, 2001; Cardona and Ruiz-Manzano, 2004). It is worthwhile to mention that WHO, international organizations, research institutions, charities and supporters altogether are working very hard to tackle different aspects of this problem and to achieve the projected targets in the coming decades. 1. Introduction Pulmonary tuberculosis (TB) is a humankind disease. Available evidence shows that some pharaohs in ancient Egypt suffered from TB and recent radiological studies using computerized tomography revealed spinal involvement in some cases. Therefore, TB is a historical disorder that had centuries of history accompanied with human life. Since the detection of tubercle bacilli as the causal agent by Robert Koch in 1882, and after the introduction of first anti-TB drugs by Schatz and Waksman in 1940, great developments have transpired in the fields of biology, microbiology, pathogenesis, immunology, drug therapy and, recently, molecular genetics of this disease and its etiological agent. However, TB is still a worldwide problem. It has been estimated, that almost one billion people have died from TB during the last 200 years (Paulson, 2013). According to the latest report, World Health Organization (WHO) declared that, in 2014, nearly 1,400,000 people had died from TB, from this number, 890,000 were men, 480,000 women and 140,000 were children. Currently, TB with HIV is the main killers globally. In the year 2014, almost 9,600,000 people had TB, 5,400,000 of whom were men, 3,200,000 women and 1 million children. Around 12% of these people were HIV positive. At the same time, 6,000,000 new cases of TB were reported by WHO, that is 63% of the total estimated figures. This means that almost 37% of patients with TB were undiagnosed and/or unreported (WHO, 2015). In 2014, 480,000 cases of multi drug-resistant (MDR) TB were estimated, while only one quarter of this number, around 123,000 were diagnosed and treated worldwide. According to the sustainable development goals (SDG), all countries are obliged to reduce the number of death from TB, 90% by the year 2030, and to reduce the number of new cases to 80%, simultaneously. In addition, all countries should plan in a manner that no family will be compromised because of this disease. Following the Oslo meeting in 1995, WHO defined two major targets as success criteria of national TB programs. First, at least 70% of patients should be diagnosed (case finding), and at least 80% of smear positive cases should be cured (cure rate). After a vast struggle and hard work at the national, regional and global level, and following the discovery of new rapid and applicable molecular diagnostic techniques and affordable therapeutic regimens, WHO has modified its strategy from “Stop TB” to “End TB“ strategy. MDR TB is defined as cases infected with tubercle bacilli that are resistant to the major essential drugs, rifampin (RIF) and isoniazid (INH), while XDR (Masjedi et al., 2006; Masjedi et al., 2008; Velayati et al., 2012; Masjedi et al., 2013) (extensively drug-resistant) refers to cases which are MDR and resistant to fluoroquinolone and two injectable drugs (amikacin and capreomycin). Recently TDR (totally drug-resistant) patterns were reported which include cases resistant to all antibiotics. These resistant cases raise difficult issues in the subject of successful control and management of tuberculosis. Although 2–3 billion of currently living people are infected with tubercle bacilli, only 5–15% of them will develop active disease during their lifetime, which is mainly pulmonary tuberculosis (Talavera et al., 2001; Tiemersma et al., 2011). This fact explains the complicated interaction between the microbe and the host, which is the subject of different branches of research (Smith, 2003). Tuberculosis bacilli are mycobacteria related to the actinomycete group (the mycobacterium TB complex) which include human and bovine types, Mycobacterium africanum, M. microtti and M. canetti. These aerobic bacilli in 80 to 90% of cases invade the lungs, and in 5 to 20% colonize other extra-pulmonary organs, mainly lymph nodes, bones and joints, and genitourinary system 9 (Tiemersma et al., 2011). The main 2. Traditional knowledge on plants used against tuberculosis Medicinal plants have been in use for centuries to cure various ailments including tuberculosis. Infusions, macerations, tinctures and decoctions of medicinal plant parts such as leaves, roots, stem bark, stem, flowers and fruits have been used for centuries as traditional treatments of TB by native people worldwide. Commercial preparations 2 Plant family Botanical name Mode of preparation/administration Locations References Acanthaceae Acanthus pubescens (Thomson ex Oliv.) Engl. Brillantaisia owariensis P. Beauv. Hygrophila auriculata (Schumach.) Heine Acanthus montanus (Nees) T.Anderson Carpobrotus edulis (L.) N.E.Br. Chenopodium ambrosioides L. Achyranthes aspera L. Amaranthus spinosus L. Allium cepa L. Roots are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and whole plant are used to treat TB and related diseases Leaf infusion is used in the treatment of TB Leaf decoction is used orally for the treatment of TB Leaves are used in curing TB and related symptoms Flowers are used to treat TB and related diseases Leaves are used to treat TB and related diseases Leaves and bulbs are used in the treatment of TB Allium sativum L. Bulbs, tubers and leaves are used for the treatment of TB and related symptoms Bulbs against coughs and colds Used for the treatment of TB Used for the treatment of TB Used for the treatment of TB Stem bark is used to treat TB and related diseases Leaves are used to treat TB Used in the treatment of TB-related diseases or their symptoms Bark is used in the treatment of TB-related diseases or their symptoms Leaf infusion is used in the treatment of TB Leaves or roots are pound, boiled and filtered for drinking Dried pound bark is boiled in water for drinking Used for the treatment of TB Used for the treatment of TB Leaf decoction and bark maceration are used in the treatment of TB Used for the treatment of TB Leaves, roots and root bark are used in the treatment of TB-related diseases or their symptoms Root bark is used for the treatment of TB symptoms and lung infections Husk decoction is used in the treatment of TB Oil soup is used in the treatment of TB Roots are used in the treatment of TB-related diseases or their symptoms Leaves are used to treat TB and related symptoms Shoots and stem (wood) are used for the treatment of TB Uganda Uganda Uganda, Ghana Nigeria South Africa South Africa, Ghana Uganda Uganda Ghana, Nigeria, South Africa South Africa, Nigeria, Ghana South Africa South Africa South Africa South Africa Uganda Kenya South Africa South Africa Nigeria Nigeria Nigeria South Africa South Africa Nigeria South Africa South Africa, Uganda, Kenya Uganda Nigeria, Ghana Nigeria South Africa Uganda South Africa, Uganda (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Nguta et al., 2015) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Nguta et al., 2015; Lall and Meyer, 1999) (Tabuti et al., 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Lawal et al., 2014; Nguta et al., 2015) (Faleyimu et al., 2009; Green et al., 2010; Tabuti et al., 2010; Nguta et al., 2015) (Madikizela, 2014) (Lawal et al., 2014) (Lawal et al., 2014) (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) (Mariita, 2006) (Green et al., 2010) (Green et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Mariita, 2006; Tabuti et al., 2010; Green et al., 2010) (Bunalema, 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010; Nguta et al., 2015) (Ogbole and Ajaiyeoba, 2010) (Green et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014; Madikizela, 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008) Aizoaceae Amaranthaceae Amaryllidace Anacardiaceae Annonaceae Apiaceae 3 Apocynaceae Brunsvigia grandiflora Lindl. Haemanthus albiflos Jacq. Tulbaghia acutiloba Harv. Tulbaghia violacea Harv. Mangifera indica L. Pistacia aethiopica Kokwaro Rhus rogersii Schönland Sclerocarya birrea (A Rich) Hochst. Spondias mombin L. Annona senegalensis Pers. Centella asiatica (L.) Urb. Centella coriacea Nannf. Daucus carota L. Alstonia boonei De Wild Araujia sericifera Brot. Carissa edulis (Forssk.) Vahl. Asparagaceae Cryptolepis sanguinolenta (Lindl.) Schltr. Cocos nucifera L. Elaeis guineensis Jacq. Asclepias fruticosa L. Gomphocarpus physocarpus E. Mey. Asparagus africanus Lam. Balanophoraceae Bignoniaceae Burseraceae Asparagus falcatus (L.) Oberm. Thonningia sanguinea Vahl. Stereospermum kunthianum Cham. Boswellia dalzielii Hutch. Arecaceae Asclepiadaceae Cannabaceae Capparaceae Commiphora africana (A.Rich.) Endl. Warburgia salutaris (G. Bertol.) Chiov. Warburgia ugandensis Sprague Caprifoliaceae Caricaceae Cannabis sativa L. Capparis erythrocarpos Isert. Capparis tomentosa Lam. Maerua edulis (Gilg & Gilg-Ben.) DeWolf. Scabiosa albanensis R.A. Dyer Carica papaya L. Caryophyllaceae Celastraceae Silene undulata Aiton Cassine papillosa (Hochst.) Kuntze Used for the treatment of TB Roots are used for the treatment of TB or symptoms Used for the treatment of TB or symptoms Tubers are used for the treatment of TB or symptoms Used for the treatment of TB Leaves and seeds are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Used to cure TB-related symptoms South Africa Nigeria Nigeria Nigeria Nigeria South Africa, Uganda Uganda, Kenya, Tanzania South Africa Uganda Uganda Uganda South Africa South Africa, Uganda (Ofukwu et al., 2008) (Tabuti et al., 2010; Green et al., 2010) (Orodho et al., 2014) South Africa South Africa (Lawal et al., 2014) (Lall and Meyer, 1999) (Lawal et al., 2014) (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Green et al., 2010) (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Canellaceae Leaves and roots are used to treat TB Fruit decoction is used in the treatment of TB Boiled leaves or bark or roots in water to drink for TB or their symptoms Bark is pounded, powdered and mixed with porridge for the treatment of TB or their symptoms Bark boiled in water for the treatment of TB or their symptoms Leaves and stem bark are used for the treatment of TB or symptoms Used for the treatment of TB or their symptoms J. Sharifi-Rad et al. Table 1 Common medicinal plants in African traditional medicine for tuberculosis treatment. Plant family Botanical name Mode of preparation/administration Locations References Clusiaceae Maytenus senegalensis (Lam.) Excell Garcinia kola Heckel; Garcinia spp. Roots and root bark are used to cure TB-related symptoms Leaf decoction is used in the treatment of TB Gloriosa superba L. Anogeissus leiocarpus (DC.) Guill. & Perr. Anogeissus schimperi Hochst. ex Hutch. & Dalziel Combretum apiculatum Sond. Combretum erythrophyllum (Burch) Sond. Combretum molle R. Br. Ex G. Don. Terminalia brownii Fresen. Terminalia phanerophlebia Engl. & Diels Terminalia sericea Burch ex D.C. Artemisia afra Jacq. ex Willd. Aspilia africana (Pers.) C. D. Adams Bidens pilosa L. Leaf decoction is used in the treatment of TB Roots boiled in water for drinking in the treatment of TB Bark socked or boiled in water to drink for the treatment of TB Dried leaves boiled for drinking in the treatment of TB Leaves used in the treatment of TB-related diseases or their symptoms Used in the treatment of TB-related symptoms Bark boiled in salted water for drinking in the treatment of TB Roots are used for the treatment of TB Bark are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Roots are used for the treatment of TB and related symptoms Flowers or whole plant are used to treat TB (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010; Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Faleyimu et al., 2009; Ofukwu et al., 2008) (Ofukwu et al., 2008) (Ofukwu et al., 2008) (Green et al., 2010) (Lall and Meyer, 1999) (Ofukwu et al., 2008) (Madikizela, 2014) (Green et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Tabuti et al., 2010; Lawal et al., 2014) Conyza ivifolia Burm.f. Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Leaves are used in the treatment of TB or related symptoms South Africa Nigeria, Uganda, Kenya Nigeria Nigeria Nigeria Nigeria South Africa South Africa Nigeria South Africa South Africa South Africa Uganda Uganda, Ghana, South Africa South Africa Uganda (Tabuti et al., 2010) Uganda South Africa (Tabuti et al., 2010) (Meyer et al., 2002) South Africa (Meyer et al., 2002) South Africa (Meyer et al., 2002) South Africa (Meyer et al., 2002) South Africa (Meyer et al., 2002) South Africa South Africa (Lall and Meyer, 1999) (Meyer et al., 2002) Uganda, South Africa Uganda South Africa South Africa South Africa Nigeria, Uganda, Kenya (Tabuti et al., 2010) (Tabuti et al., 2010) (Lall and Meyer, 1999) (Lall and Meyer, 1999) (Lall and Meyer, 1999) (Mariita, 2006; Ofukwu et al., 2008; Tabuti et al., 2010) South Africa (Meyer et al., 2002) Nigeria Nigeria Nigeria Uganda Nigeria Uganda Uganda Kenya Ghana Uganda (Ogbole and Ajaiyeoba, (Ogbole and Ajaiyeoba, (Ogbole and Ajaiyeoba, (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, (Tabuti et al., 2010) (Tabuti et al., 2010) (Mariita, 2006) (Nguta et al., 2015) (Tabuti et al., 2010) Colchicaceae Combretaceae Asteraceae Conyza sumatrensis (Retz.) E. Walker (syn. C. floribunda) Gutenbergia cordifolia Benth. ex Oliv. Helichrysum appendiculatum (L.f.) Less. Helichrysum caespititium (DC.) Sond. ex Harv. 4 Helichrysum imbricatum (L.) Less. Helichrysum krausii Sch.Bip. Helichrysum leiopodium DC. Helichrysum melanacme DC. Helichrysum nudifolium (L.) Less. Helichrysum odoratissimum (L.) Sweet Microglossa pyrifolia (Lam.) Kuntze Nidorella anomala Steetz. Nidorella auriculata DC. Senecio serratuloides DC. var. serratuloides Vernonia amygdalina Delile Convolvulaceae Costaceae Crassulaceae Cucurbitaceae Cyperaceae Ipomoea batatas (L.) Lam. Ipomoea involucrata P·Beauv. Costus afer Ker Gawl. Kalanchoe spp. Bryophyllum pinnatum (Lam.) Oken Momordica foetida Schum. Lagenaria sphaerica (Sond.) Naudin Momordica charantia L. Cyperus articulatus L. Cyperus latifolius Poir. (Meyer et al., 2002) 2010) 2010) 2010) 2010) (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Vernonia woodii O·Hoffm. Roots and leaves are used for the treatment of TB and related symptoms Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Exudates are used against TB and related disorders, such as bronchopneumonial diseases, and symptoms such as cough, fever, blood in the sputum The tea and infusion are used as a demulcent in coughs and in pulmonary affections The smoke of dried flowers and seeds in a pipe is used for the relief of cough and as a remedy for TB Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Used in the treatment of TB-related symptoms Tea and infusion are used as a demulcent in coughs and in pulmonary affections Leaves are used in the treatment of TB-related symptoms Roots are used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Pounded fresh leaves fresh and squeezed for drinking are used in the treatment of TB-related symptoms. Root barks used to treat TB and asthma Used in the treatment of TB-related symptoms such as cough, fever, blood in the sputum Peeling maceration is used in the treatment of TB Leaf infusion is used to cure TB Stem decoction and leaf infusion are used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Leaf infusion is used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Whole plant is used to treat asthma, TB, and pneumonia Roots are used to treat TB Roots are used in the treatment of TB-related symptoms J. Sharifi-Rad et al. Table 1 (continued) J. Sharifi-Rad et al. Table 1 (continued) Botanical name Mode of preparation/administration Locations References Ebanaceae Cyperus rotundus L. ssp. rotundus Diospyros mespiliformis Hochst Roots are used in the treatment of TB-related symptoms Leaves/bark are used in the treatment of TB-related diseases or their symptoms Used in the treatment of TB-related symptoms Roots are used in the treatment of TB-related symptoms Bark is used in the treatment of TB-related diseases or their symptoms Stem bark is used to treat TB, asthma, and coughs Leaves are used to treat TB Used to treat TB-related symptoms Stems are used to treat common cold and TB Leaves are used in the treatment of TB-related symptoms Stems are used to treat TB and asthma Roots are used in the treatment of TB-related symptoms Roots are used in the treatment of TB-related symptoms Roots are used to treat coughs and TB Roots are used in the treatment of coughs and tuberculosis Used in the treatment of TB-related symptoms Used for the treatment of TB Used for the treatment of TB or symptoms Bulb tincture is used to cure TB Leaves are used in the treatment of TB-related symptoms Leaf decoction is used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Leaves and stem (wood) are used in the treatment of TB-related symptoms Leaves and stems are used in the treatment of colds, coughs, bronchitis, asthma and TB Leaves are used in the treatment of TB-related symptoms Used for the treatment of TB Bulb is boiled in water for drinking and used in the treatment of TB-related symptoms. Leaf tincture is used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Used for the treatment of TB Used to cure TB-related symptoms Leaves, stem (wood) and seeds are used in the treatment of TB-related symptoms Leaves and roots are used to treat TB, bronchitis, whooping cough, chest complaints and asthma. Seed decoction is used in TB treatment Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark, stem (wood) and fruits are used in the treatment of TB-related symptoms Used for the treatment of TB Stem bark is used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Stem bark is used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Bark infusion is used to cure TB Fairly dried leaves boiled for drinking in the treatment of TB-related symptoms Uganda South Africa (Tabuti et al., 2010) (Green et al., 2010) South Africa Uganda South Africa Kenya Kenya South Africa Kenya Uganda Kenya Uganda Uganda South Africa South Africa South Africa South Africa Uganda Nigeria Uganda Nigeria Uganda Uganda Uganda South Africa (Lall and Meyer, 1999) (Tabuti et al., 2010) (Green et al., 2010) (Mariita, 2006) (Mariita, 2006) (Lall and Meyer, 1999) (Mariita, 2006) (Tabuti et al., 2010) (Mariita, 2006) (Tabuti et al., 2010) (Tabuti et al., 2010) (Mativandlela et al., 2006) (Mativandlela et al., 2006) (Lall and Meyer, 1999) (Lawal et al., 2014) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Madikizela, 2014) Uganda South Africa Nigeria (Tabuti et al., 2010) (Lawal et al., 2014) (Ofukwu et al., 2008; Ogbole and Ajaiyeoba, 2010) Uganda Uganda Uganda South Africa South Africa Uganda (Tabuti et al., 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Lall and Meyer, 1999) (Tabuti et al., 2010) South Africa, Nigeria (Ogbole and Ajaiyeoba, 2010; Madikizela, 2014) Nigeria Nigeria Uganda (Faleyimu et al., 2009) (Faleyimu et al., 2009) (Tabuti et al., 2010; Orodho et al., 2014) South Africa Uganda Nigeria Uganda South Africa Uganda Nigeria Nigeria (Lawal et al., 2014) (Tabuti et al., 2010) (Faleyimu et al., 2009) (Tabuti et al., 2010) (Lall and Meyer, 1999) (Orodho et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ofukwu et al., 2008) Euphorbiaceae Geraniaceae Gunneraceae Hypoxidaceae Hypericaceae Iridaceae Lamiaceae 5 Euclea natalensis A. DC. Euclea divinorum Hiern. Bridelia micrantha (Hochst.) Baill. Croton macrostachyus Hochst. ex Ferret et Galinier Croton megalocarpus Hutch. Croton pseudopulchellus Pax Euphorbia scarlatica (L) O. Kuntz Euphorbia schimperiana Scheele Euphorbia tirucalli L. Tragia brevipes Pax Tragia subsessilis Pax Pelargonium sidoides DC. Pelargonium reniforme Curtis Gunnera perpensa L. Hypoxis argentea Harv. ex Baker Hypericum revolutum Vahl Zygotritonia bongensis (Pax) Mildbr Achyrospermum carvalhoi Gürke Clerodendrum capitatum (Willd.) Schum. & Thonn Hoslundia opposita Vahl Iboza multiflora (Benth.) E. A. Bruce Iboza riparia (Hochst.) N. E. Br. Leonotis intermedia Lindl. Leonotis nepetifolia (L.) R. Br. Mentha longifolia (L.) L. Ocimum gratissimum L. Lauraceae Leguminosae (Fabaceae) Ocimum suave Willd. Plectranthus barbatus Andr. Pycnostachys erici-rosenii R.E.Fr. Rosmarinus officinalis L. Cryptocarya latifolia Sond. Persea americana Mill. Abrus precatorius L. Acacia albida Delile Acacia hebecladoides Harms Acacia hockii De Wild. Acacia karroo Hayne Acacia mearnsii De Wild. Acacia nilotica (L.) Delile Acacia polyacantha Willd. Acacia xanthophloea Benth. Albizia coriaria Oliv. Baphia nitida Lodd. Cassia alata L. (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Plant family Plant family Loranthaceae Malvaceae Melastomataceae 6 Meliaceae Menispermaceae Moraceae Moringaceae Musaceae Myristicaceae Myrsinaceae Myrtaceae Polygalaceae Polygonaceae Primulaceae Mode of preparation/administration Locations References Cassia occidentalis L. Cassia petersiana Bolle Desmodium repandum (Vahl) DC. Entada abbysinica A. Rich. Erythrina abyssinica Lam. ex DC. Nigeria South Africa Uganda Kenya, Tanzania Uganda, Kenya, Tanzania South Africa Nigeria Uganda Uganda South Africa Nigeria Uganda South Africa Uganda Uganda, Nigeria Nigeria Nigeria (Ofukwu et al., 2008) (Green et al., 2010) (Tabuti et al., 2010) (Orodho et al., 2014) (Mariita, 2006; Tabuti et al., 2010; Bunalema, 2010; Orodho et al., 2014) (Madikizela, 2014) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Green et al., 2010) (Faleyimu et al., 2009) (Tabuti et al., 2010) (Green et al., 2010) (Tabuti et al., 2010) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ofukwu et al., 2008) (Ofukwu et al., 2008; Faleyimu et al., 2009) Ficus sur Forssk Moringa oleifera Lam. Musa nana Lour. Pycnanthus angolensis (Welw.) Warb. Maesa lanceolata Forssk. Callistemon citrinus (Curtis) Skeels Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson Eucalyptus spp. Dried leaves boiled for drinking in the treatment of TB-related symptoms Bark is used in the treatment of TB-related diseases or their symptoms Leaves are used for the treatment of TB symptoms and pulmonary infections Used in the treatment of TB-related symptoms Root and stem barks are used for the treatment of TB symptoms and pulmonary infections Roots are used in the treatment of TB-related symptoms Leaf infusion is used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Roots are used in the treatment of TB-related symptoms Bark is used in the treatment of TB-related diseases or their symptoms Used in the treatment of TB-related symptoms Stem (wood) is used in the treatment of TB-related symptoms Bark used in the treatment of TB-related diseases or their symptoms Stem bark is used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Leaves, Bark boiled in water for drinking in the treatment of TB Dried leaves boiled in water for drinking 2 times for 24 days only in the treatment of TB Fresh leaves is boils in water for drinking and are used in the treatment of TB Roots are used in the treatment of TB-related diseases or their symptoms Fruit infusion is used in the treatment of TB Leaf decoction is used in TB treatment Leaf is used in the treatment of TB Leaves are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB Seeds, leaves, stem (wood) and stem bark are used in the treatment of TB Used in the treatment of TB-related symptoms Leaf infusion is used in the treatment of TB Leaf maceration is used in TB treatment Stem bark, squeezed fresh leaves or boiled for drinking in the treatment of TB-related symptoms Bark and roots are used to treat TB and lung ulceration Seeds are used in the treatment of TB-related symptoms Leaf meal is used in the treatment of TB Bark maceration is used in TB treatment Roots are used in the treatment of TB-related symptoms Leaves are used in the treatment of TB-related symptoms Used for the treatment of TB Leaves and stem bark are used in the treatment of TB-related symptoms (Ofukwu et al., 2008) (Green et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Nguta et al., 2015) (Tabuti et al., 2010; Nguta et al., 2015) (Lall and Meyer, 1999) (Ogbole and Ajaiyeoba, 2010) (Hannan et al., 2011) (Ofukwu et al., 2008; Tabuti et al., 2010; Lawal et al., 2014) (Lawal et al., 2014) (Madikizela, 2014) (Faleyimu et al., 2009; Tabuti et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010; Orodho et al., 2014) Psidium guajava L. Syzygium cordatum Hochst. ex Krauss Ximenia caffra Sond. var. caffra Alectra sessiliflora (Vahl) Kuntz Phyllanthus fraternus G.L. Webster Piper capense L.f. Coix lacryma-jobi L. Cymbopogon giganteus Chiov. Cymbopogon citratus (DC.) Stapf. Polygala fruticosa P.J. Bergius Polygala myrtifolia L. Securidaca longipedunculata Fresen. Rumex crispus L. Rapanea melanophloeos (L.) Mez. Bark maceration is used in the treatment of TB Used for the treatment of TB Leaves are used in the treatment of TB-related diseases or their symptoms Leaf infusion is used in TB treatment Leaves are used in the treatment of TB Roots used in the treatment of TB-related diseases or their symptoms Glumes are used in the treatment of TB Leaves are used in the treatment of TB Leaf infusion is used in TB treatment Whole plant is used in TB treatment Used in the treatment of TB-related symptoms Roots are used in the treatment of TB-related diseases or their symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Nigeria South Africa Nigeria Nigeria Nigeria Uganda Ghana Ghana, Uganda South Africa Nigeria Nigeria Nigeria, Uganda, South Africa South Africa Uganda, Nigeria Nigeria Nigeria Uganda Uganda South Africa Uganda, Kenya, Tanzania Nigeria South Africa South Africa Nigeria Ghana South Africa Ghana Ghana Nigeria South Africa South Africa South Africa, Uganda South Africa South Africa Indigofera arrecta Benth. ex Harv. & Sond. Lonchocarpus cyanescens (Schumach. & Thonn.) Benth. Mucuna pruriens (L.) DC. Ormocarpum trichocarpum (Taub.) Harms Peltophorum africanum Sond Piliostigma reticulatum (DC.) Hochst. Piliostigma thonningii (Schumach.) Milne-Redh. Schotia brachypetala Sond Senna siamea (Lam.) Irwin & Barneby Tamarindus indica L. Tapinanthus dodoneifolius (DC.) Danser Adansonia digitata L. Ceiba pentandra (L.) Gaertn. Grewia villosa Willd. Cola acuminata (P·Beauv.) Schott & Endl. Glyphaea brevis (Spreng.) Monach. Hibiscus sabdariffa L. Antherotoma senegambiensis (Guill. & Perr.) Jacq.-Fél. Dissotis rotundifolia (Sm.) Triana Azadirachta indica A. Juss. Ekebergia capensis Sparm. Jateorhiza macrantha (Hook.f.) Exell & Mendonça Ficus asperifolia Miq. Ficus platyphylla Delile (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Green et al., 2010) (Ogbole and Ajaiyeoba, 2010) (Nguta et al., 2015) (Green et al., 2010) (Nguta et al., 2015) (Nguta et al., 2015) (Ogbole and Ajaiyeoba, 2010) (Madikizela, 2014) (Lall and Meyer, 1999) (Tabuti et al., 2010; Green et al., 2010) (Lall and Meyer, 1999) (Lall and Meyer, 1999) (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Olacaceae Orobanchaceae Phyllanthaceae Piperaceae Poaceae Botanical name J. Sharifi-Rad et al. Table 1 (continued) Botanical name Mode of preparation/administration Locations References Rhamnaceae Berchemia discolor (Klotzsch) Hemsl. Bark/leaves are used in the treatment of TB-related diseases or their symptoms Leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Bark, leaves and roots are used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Leaves are used in the treatment of TB-related diseases or their symptoms Roots are used in the treatment of TB-related diseases or their symptoms South Africa (Green et al., 2010) Uganda (Tabuti et al., 2010) South Africa (Green et al., 2010; Lawal et al., 2014) South Africa Uganda Uganda (Lawal et al., 2014) (Tabuti et al., 2010) (Tabuti et al., 2010) South Africa Uganda, Kenya South Africa South Africa Nigeria Nigeria South Africa Uganda South Africa Uganda Kenya Uganda, Kenya Kenya Uganda Uganda South Africa Nigeria South Africa Kenya Ghana South Africa Kenya Uganda Kenya Kenya Uganda (Madikizela, 2014) (Orodho et al., 2014) (Lawal et al., 2014) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Lawal et al., 2014) (Tabuti et al., 2010) (Mariita, 2006) (Madikizela, 2014; Orodho et al., 2014) (Mariita, 2006) (Tabuti et al., 2010) (Tabuti et al., 2010) (Lawal et al., 2014) (Ogbole and Ajaiyeoba, 2010) (Lawal et al., 2014) (Bunalema, 2010; Orodho et al., 2014) (Nguta et al., 2015) (Lawal et al., 2014) (Mariita, 2006) (Tabuti et al., 2010) (Mariita, 2006) (Mariita, 2006) (Tabuti et al., 2010) South Africa, Uganda (Tabuti et al., 2010; Green et al., 2010) Ghana Ghana, Uganda Nigeria Uganda (Nguta et al., 2015) (Tabuti et al., 2010; Nguta et al., 2015) (Ogbole and Ajaiyeoba, 2010) (Tabuti et al., 2010) Rhamnus prinoides L'Herit. Ziziphus mucronata Willd. Rosaceae Rubiaceae Rutaceae Sapindaceae 7 Sapotaceae Solanaceae Verbenaceae Vitaceae Xanthorrhoeaceae Zingiberaceae Zygophyllaceae Prunus africana (Hook.f.) Kalkman Coffea spp. Gardenia ternifolia Schumach. & Thonn. ssp. jovistonantis (Welw.) Hiern. Pentanisia prunelloides Schinz Rubia cordifolia L. Rubia petiolaris DC. Agathosma betulina (P.J.Bergius) Pillans Citrus aurantifolia (Christm.) Swingle Citrus medica L. Clausena anisata (Willd.) Hook.f. ex Benth. Harrisonia abyssinica Oliv. Ptaeroxylon obliquum (Thunb.) Radlk. Teclea nobilis Del. Toddalia asiatica (L.) Lam. Zanthoxylum chalybeum Engl. Zanthoxylum gillettii De Wild. Waterm. Dodonaea angustifolia L. f. Haplocoelum foliolosum (Heirn) Bullock Hippobromus pauciflorus Radlk. Vitellaria paradoxa C.F·Gaertn Capsicum frutescens L. Solanum incanum L. Solanum torvum Sw. Withania somnifera (L.) Dunal Clerodendrum myricoides (Hochst) Vatke Lantana trifolia L. Lantana camara L. Lantana trifolia L. Cyphostemma cyphopetalum (Fresen.) Desc. Ex Wild & Drumm. Rhoicissus tridentata (L.f.) Wild & R.B.Drumm. Aloe vera var. barbadensis Zingiber officinale Roscoe Aframomum melegueta (Roscoe) K·Schum. Balanites aegyptiaca (L.) Delile Roots are used to treat TB and chest disorders Used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Used for the treatment of TB Fruit infusion is used in TB treatment Fruit infusion is used in TB treatment Used for the treatment of TB Root bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Leaves are used in the treatment of TB-related diseases or their symptoms Roots are used to treat TB Roots are used in the treatment of TB-related diseases or their symptoms Stem bark is used to treat TB and asthma Leaves are used in the treatment of TB-related diseases or their symptoms Stem bark is used in the treatment of TB-related diseases or their symptoms Used for the treatment of TB Oil decoction is used in TB treatment Used for the treatment of TB Fruits are used in the treatment of TB symptoms and chest-related infections Unripe fruits/leaves are used to treat TB Used for the treatment of TB Roots are used to treat TB and chest disorders Leaves are used for the treatment of TB and related symptoms Leaves are used to treat TB, pneumonia, and chest pains Leaves are used to treat TB and cough Stem (wood), leaves and tubers are used in the treatment of TB-related diseases or their symptoms Tubers, leaves and stem (wood) are used in the treatment of TB-related diseases or their symptoms Leaves are used in the treatment of TB Rhizomes are used in TB treatment Fruit tincture is used in TB treatment Stem bark and roots are used in the treatment of TB-related diseases or their symptoms Biotechnology Advances xxx (xxxx) xxx–xxx Plant family J. Sharifi-Rad et al. Table 1 (continued) Plant family Botanical name Mode of preparation/administration Locations References Acanthaceae Adhatoda vasica Nees Leaves, flowers and roots are used for the treatment of asthma, gasping cough, bronchitis, cold and TB. Leaf juice (30 mL) with honey removes mucus from lungs Ground leaves with mortar and pestle, served with honey for TB treatment Ayurveda (Ayyanar and Ignacimuthu, 2008; Arya, 2011; Debnath et al., 2012; Gautam et al., 2012; Alvin et al., 2014; Tewari et al., 2015) Amaranthaceae Amaryllidaceae Andrographis paniculata (Burm.f.) Nees Spinacia oleracea L. Allium cepa L. Allium sativum L. Apiaceae Centella asiatica (L.) Urb. Apocynaceae Arecaceae Hemidesmus indicus R.Br Tabernaemontana coronaria (L.) Willd. Borassus flabellifer L. Berberidaceae Licuala spinosa Thunb. Berberis aristata DC. Boraginaceae Brassicaceae Burseraceae 8 Calophyllaceae Caryophyllaceae Heliotropium indicum L. Nasturtium indicum (L.) DC. Commiphora mukul (Hook. ex Stocks) Engl. Mesua ferrea L. Pseudostellaria heterophylla (Miq.) Pax Stellaria rubra Scop. Terminalia chebula Retz Commelinaceae Compositae (Asteraceae) Rhoeo spathacea (Sw.) Stearn Eclipta prostrata L. Crassulaceae Pluchea indica (L.) Less. Saussurea lappa (Decne.) Sch.Bip. Taraxacum officinale F.H. Wigg Kalanchoe integra (Medik.) Kuntze Benincasa hispida (Thunb.) Cogn. Trichosanthes dioica Roxb. Acalypha indica L. Euphorbiaceae Flacourtiaceae Gentianaceae Jatropha curcas L. Mallotus philippensis (Lam.) Müll.Arg. Ricinus communis L. Hydnocarpus anthelminthica Pierre ex Laness Canscora decussata (Roxb.) Schult. & Schult.f. (Ahmed, 2016) (Arya, 2011) (Arya, 2011; Viswanathan et al., 2014; Ahmed, 2016) Ayurveda, Indonesia Ayurveda Malaysia (Ayyanar and Ignacimuthu, 2008; Alvin et al., 2014) Ayurveda (Samal, 2016) Malaysia Ayurveda (Mohamad et al., 2011) (Samal, 2016) Arabian Peninsula Indonesia Ayurveda (Saganuwan, 2010) (Alvin et al., 2014) (Dhanabal et al., 2015) Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Roots are used to treat TB Ayurveda (Samal, 2016) Ayurveda (Chandra and Rawat, 2015) Whole plant juice rich in vitamin C is used in treatment of weakness after illness, lung congestion and TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Boiled water leaf extract is used for TB treatment Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Boiled water leaf and root extracts are used for TB treatment Roots are used in Rasayana capsules as 1/2 part in adjuvant therapy for TB Leaf decoction is taken orally against TB Leaves are used in the treatment of TB Remedy against TB Roots and fruits are used in the treatment of TB Leaves are used as expectorant, diuretic, respiratory disease, pneumonia, asthma and TB Stem bark decoction (30–50 mL) is taken orally thrice a day for TB treatment Glandular trichomes and hairs of fruit are used in the treatment of TB Ayurveda (Chandra and Rawat, 2015) Ayurveda (Samal, 2016) Indonesia Ayurveda (Alvin et al., 2014) (Samal, 2016) Indonesia Ayurveda Iraq Ayurveda Philippine Ayurveda Ayurveda (Alvin et al., 2014) (Samal, 2016) (Ahmed, 2016) (Arya, 2011) (Batugal et al., 2004) (Arya, 2011) (Arya, 2011; Dhanabal et al., 2015) Ayurveda Ayurveda (Poonam and Singh, 2009) (Arya, 2011) Boiled water extract of leaves and roots are used for TB Seeds are used against leprosy and TB Indonesia Chinese (Alvin et al., 2014) (Wang et al., 2010) Roots are used in the treatment of TB Ayurveda (Namita and Mukesh, 2012) Old cane jaggery is used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Leaves are used to treat TB Hydroalcoholic extract is used as part of 200 mg Liv-600 capsule administer thrice a day as adjuvant therapy for TB (hepatoprotective properties) Leaves, flowers or roots decoctions to treat TB Boiled water extract of all aerial parts is used for TB treatment Used for centuries. Commercial products are promoted for use in TB (Samal, 2016) (Mohamad et al., 2011) (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Combretaceae Indonesia Iraq Ayurveda Iraq, Ayurveda Leaf decoction is taken orally against weight loss and TB Bulbs are used for the treatment of asthma, cough, bronchitis and TB Bulbs are used for the treatment of asthma, cough, bronchitis and TB Decoction of bulbs is used orally to treat TB Whole plant is used for leprosy, bronchitis, asthma and TB. Boiled water extract of ground plant (all aerial parts) is used for TB treatment Root is used in Rasayana as adjuvant therapy for TB Leaves are used to treat TB J. Sharifi-Rad et al. Table 2 Common medicinal plants used in Asia for tuberculosis treatment. Plant family Botanical name Mode of preparation/administration Locations References Lamiaceae Colebrookea oppositifolia Sm. Ocimum sanctum L. Vitex negundo L. Vitex trifolia L. Cinnamomum cassia (Nees & T.Nees) J.Pres Cinnamomum tamala (Buch.-Ham.) T.Nees & Eberm. Ayurveda Ayurveda Ayurveda Ayurveda, Indonesia Iraq (Namita and Mukesh, 2012) (Namita and Mukesh, 2012) (Namita and Mukesh, 2012; Ahuja et al., 2015) (Batugal et al., 2004; Arya, 2011; Alvin et al., 2014) Lauraceae Leaves, fruits and roots are used in the treatment of TB Leaves, flowers and seeds are used in the treatment of TB Leaves and seeds as well as a decoction of the stem bark is used to treat TB Leaves, roots and fruits are used in the treatment of TB. Boiled water extract of leaves is used for TB treatment Powder of stem bark is used against cough and TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Leaves are used to treat cough, respiratory tract infections, bronchitis Leaves and flowers are used in the treatment of TB Boiled water extract of chopped pieces is used for TB Leaves are used to treat respiratory diseases including symptoms of TB Roots to treat TB. Roots are used in Rasayana capsules as 1 parts in adjuvant therapy for TB Leaves and roots are used in the treatment of TB Oil, leaves, roots and seeds are used as cough suppressant, to treat asthma, pneumonias and TB Roots are useful in TB, cough and bronchitis Boiled water extract of leaves is used for TB treatment Stem and leaves benefit the general weakness and TB. Used in Rasayana capsules as 1 parts in adjuvant therapy of TB Leaves are used to treat TB Ayurveda (Samal, 2016) Ayurveda (Samal, 2016) Ayurveda Ayurveda Indonesia Malaysia Chinese, Ayurveda (Gautam et al., 2012) (Arya, 2011) (Alvin et al., 2014) (Mohamad et al., 2011) (Namita and Mukesh, 2012; Samal, 2016) Ayurveda Arabian Peninsula (Arya, 2011) (Saganuwan, 2010) Ayurveda Indonesia Ayurveda (Nair, 1998; Warrier, 2002) (Alvin et al., 2014) (Dhanabal et al., 2015; Samal, 2016) Malaysia (Mohamad et al., 2011) Ayurveda Ayurveda (Poonam and Singh, 2009) (Samal, 2016) Ayurveda Ayurveda (Arya, 2011) (Samal, 2016) Philippines Ayurveda Ayurveda (Batugal et al., 2004) (Samal, 2016) (Samal, 2016) Ayurveda Ayurveda Ayurveda Arabian Pennisula Ayurveda (Tewari et al., 2015) (Nair, 1998; Warrier, 2002) (Nair, 1998; Warrier, 2002) (Saganuwan, 2010) (Arya, 2011; Samal, 2016) Arabian Peninsula Philippine Philippine Arabian Peninsula Ayurveda Chinese (Saganuwan, 2010) (Batugal et al., 2004) (Batugal et al., 2004) (Saganuwan, 2010) (Arya, 2011) (Zhang et al., 2015) Cinnamomum zeylanicum Blume Leguminosae (Fabaceae) Acacia senegal (L.) Willd. Caesalpinia pulcherrima (L.) Sw. Caesalpinia sappan L. Flemingia strobilifera (L.) W.T. Aiton Glycyrrhiza glabra L. Mimosa pudica L. Trigonella foenum-graecum L. Asparagus racemosus Willd. Hibiscus tilliaceus L. Tinospora cordifolia (Willd.) Miers Meliaceae Myristicaceae Tinospora crispa (L.) Miers ex Hook. f. & Thoms. Azadirachta indica Juss. A. Myristica fragrans Houtt. 9 Liliaceae Malvaceae Menispermaceae Myrtaceae Myrtus communis L. Syzygium aromaticum (L.) Merr. & L.M.Perry Ophioglossaceae Phyllanthaceae Helmintostachys zeylanica (L.) Hook. Emblica officinalis Gaertn. Phyllanthus fraternus G.L. Webster Pinaceae Plantaginaceae Poaceae Polygonaceae Ranunculaceae Plantago major L. Imperata cylindrical (L.) Raeuschel Saccharum spontaneum L. Sorghum bicolor (L.) Moench Rumex hastatus D. Don Ranunculus ternatus Thunb. (Ahmed, 2016) (continued on next page) Biotechnology Advances xxx (xxxx) xxx–xxx Piperaceae Emblica officinalis Gaertn. Cedrus deodara Roxb. Pinus contorta Douglas. ex Loudon. Pinus pinea L. Piper longum L.; Piper spp. Leaf paste is used against TB, 1 tea spoon twice a day by oral route. Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Fruits are used in the treatment of TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Used to treat TB Pericarp is used in Rasayana capsules as 1 parts in adjuvant therapy for TB Freshly prepared decoction of aerial parts is used as part of 10 mg and administered thrice a day as adjuvant therapy of TB Fruit juice is useful for cough, asthma and TB Leaves are used in the treatment of TB The inner bark to treat TB Leaves, roots and stem are used to treat TB Fruit is used in Rasayana capsules as 1/2 parts in adjuvant therapy of TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Fruits and leaves are used to treat TB, hemorrhage and pneumonia Rhizome decoction is used to treat TB To treat TB Seeds, flowers and leaves are used to treat cough and TB Root and bark are used in the treatment of TB Roots are used alone or combined with other herbal remedies in the treatment of TB. Radix Ranunculi Ternati is now the only commercially available medicine for the J. Sharifi-Rad et al. Table 2 (continued) Biotechnology Advances xxx (xxxx) xxx–xxx (Saganuwan, 2010) (Arya, 2011) (Nair, 1998; Warrier, 2002) (Batugal et al., 2004) (Arya, 2011; Tewari et al., 2015) (Alvin et al., 2014) (Arya, 2011) (Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Alvin et al., 2014) (Samal, 2016) (Samal, 2016) (Samal, 2016) (Batugal et al., 2004) Arabian Pennisula Ayurveda Ayurveda Philippine Ayurveda Indonesia Ayurveda Indonesia Ayurveda Ayurveda Indonesia Ayurveda Ayurveda Ayurveda Philippine of some of these remedies are available and continue to be used with considerable success in affected communities. Even though ethnobotanical and ethnopharmacological studies confirmed their wide use in the treatment of TB, the therapeutic and safe doses are still to be established for most of them. Most of the studies also failed to provide scientific evidence to traditional beliefs and therapeutic practices. Therefore, this work is an attempt to document medicinal plants traditionally used to control TB. Different traditional healing systems have been applied to cure TB, ranging from the poor documented oral African medicine to the well documented Asian or Chinese, Ayurveda and so on. 2.1. Indigenous knowledge on tuberculosis The unique and exclusive indigenous knowledge in Africa is orally transferred to the next generation especially in rural communities (Lawal et al., 2014). Tuberculosis is believed to be a contagious disease transmitted mainly through sharing contaminated food and eatingutensils, and droplet infection is known by the African traditional system by signs and symptoms that include cough, wheezing cough, labored breathing and weight loss (Tabuti et al., 2010). However, some of these symptoms are not specific and can be related to other pulmonary diseases such as asthma, different infections, cancer and ordinary cough. In Ayurveda (Indian traditional medicine system), TB is aptly referred as Rajayakshma, a disease of grave prognosis, along with ascites and marasmus, that spreads from one person to another (Jayana) like the flight of birds. It is attributable to tissue emaciation or loss (Dhatukshaya) involved in pathogenesis accompanied by metabolic dysfunction (Dhatwagninasana): fluid, blood, muscle, adipose tissue and generative tissue are lost leading to immunosuppression (Debnath et al., 2012; Samal, 2016). Conventional anti-TB medications have been prescribed to control symptoms, but they result in side effects and, therefore, the use of herbal medicine has been promoted (Arya, 2011). Finally, traditional Chinese medicine cure TB by combining antibacterial treatments, strengthening QI (vital energy) and administering herbs to protect the liver (Liu et al., 2008). A total of 222 plant species used in Africa for TB treatment were recorded, belonging to 71 families (Table 1). The families with the most species of plants used to cure TB are Leguminosae (or Fabaceae, 28 species) and Compositae (or Asteraceae, 20 species) (Table 1). Overall, the most frequently used plant parts are leaves, whole root and stem bark (Tabuti et al., 2010). The most frequently cited species are Erythrina abyssinica Lam. ex DC. and Allium sativum L. (4 occurrences), Ficus platyphylla Delile, Bidens pilosa L., Asparagus africanus Lam., Carissa edulis (Forssk.) Vahl. and Allium cepa L. (3 occurrences) (Table 1). The anti-TB activity of E. abyssinica and A. sativum has been demonstrated extensively. E. abyssinica crude methanol extract showed antimicrobial activity on the sensitive strain H37Rv and the rifampicin resistant strain TMC-331, with MIC values of 0.39 mg/mL and 2.35 mg/ mL, respectively (Bunalema, 2010). A. sativum extract inhibited both non-MDR and MDR M. tuberculosis isolates, with MIC values ranging from 1000 to 3000 μg/mL (Hannan et al., 2011). The leaf ethanol extract of B. pilosa exhibited activity against M. tuberculosis at 100 μg/mL (Gautam et al., 2007). C. edulis showed antibacterial activity against slow (M. tuberculosis, M. kansasii) and fast (M. fortuitum and M. smegmatis) growing mycobacteria (Mariita, 2006). A. cepa anti-mycobacterial activities have previously been reported (Arya, 2011). Kaempferia galanga L. Withania somnifera L. Lantana camara L. Alpinia galanga (L.) Willd. Curcuma longa L. Elettaria cardamomum (L.) Maton 2.2. Medicinal plants used in African traditional medicine for the management of tuberculosis Verbenaceae Zingiberaceae Rubiaceae Salicaceae Simaroubaceae Solanaceae treatment of TB Leaves, oil and flowers are used to treat TB and cough Kernels are used in the treatment of TB A decoction of the roots is used in the treatment of TB Remedy against incipient TB, hemorrhage and headache Leaves, roots and fruits are used in the treatment of TB Boiled water extract of aerial parts are used for TB treatment Leaves, roots, bark and fruits are used in TB treatment Ground fruits with mortar and pestle for TB treatment Hydroalcoholic extract is used as part of 200 mg capsules Liv-600 administered thrice a day as adjuvant therapy of TB Root is used in Rasayana capsules as 1 parts in adjunct treatment of TB Boiled water extract of leaves and flowers are used for TB treatment Rhizome is used in Rasayana capsules as 1/4 part in adjuvant therapy of TB Rhizome is used in Rasayana capsules as 1/2 part in adjuvant therapy of TB Used in Bhringarajasava, a liquid formulation (30 mL) administered in an equal quantity of water, 30 min after meal, thrice a day during the intensive phase of TB treatment and followed up to 6–8 months Whole plant is used as remedy for common cold, bronchitis and TB Prunus amygdalus Batsch Prunus armeniaca L. Rubus occidentalis L. Ixora chinensis Lam. Morinda citrifolia L. Morinda citrifolia L. Flacourtia ramontchi L'Hér. Brucea javanica (L.) Merr. Solanum nigrum L. Rosaceae Botanical name Plant family Table 2 (continued) Mode of preparation/administration Locations References J. Sharifi-Rad et al. 2.3. Medicinal plants used in Asian traditional medicine for the management of tuberculosis From Asian traditional medicine including Ayurveda, 84 plant 10 Botanical name Mode of preparation/administration Locations References Amaranthaceae Chenopodium ambrosiodes L. Brazil, Amazonia Apocynaceae Aspidosperma carapanauba Pichon. Parahancornia amapa (Huber) Ducke Aspidosperma carapanauba Pichon Aloe arborescens Mill. Aloe vera (L.) Burm.f. 1 bunch of fresh leaves in 500 mL water as juice/syrup/condensed milk/tea, daily dosage 200/400 mL, for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms Syrup and juice are indicated for the treatment of lung problems, cough and TB Leaves and gel from leaves are used in the treatment of TB. Hydroalcoholic extract as parts of 200 mg capsule Liv-600 administered thrice a day as adjuvant therapy for TB Stem bark is used in treating TB Used in the treatment of TB-related symptoms Syrup and juice are indicated for the treatment of lung problems, cough and TB Leaves are used to treat bronchitis and TB Tea is indicated for the treatment of lung problems, cough and TB Tea is indicated for the treatment of lung problems, cough and TB Tea is indicated for the treatment of lung problems, cough and TB Tea and syrup are indicated for the treatment of lung problems, cough and TB Amazonia Amazonia Amazonia Brazil Ayurveda (Storey and Salem, 1997; Leitão et al., 2013) (Storey and Salem, 1997) (Storey and Salem, 1997) (Storey and Salem, 1997) (Leitão et al., 2013) (Arya, 2011; Samal, 2016) South Pacific Amazonia Brazil Tahiti Brazil Brazil Brazil Brazil (WHO, 1998) (Storey and Salem, 1997) (Leitão et al., 2013) (WHO, 1998) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) Tea and juice are indicated for the treatment of lung problems, cough and TB Brazil (Leitão et al., 2013) Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Juice is indicated for the treatment of lung problems, cough and TB Juice is indicated for the treatment of lung problems, cough and TB Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Syrup is indicated for the treatment of lung problems, cough and TB Tea and syrup are indicated for the treatment of lung problems, cough and TB A handful of fresh leaves and flowers in 500 mL water as juice/condensed milk, daily dosage ad libitum Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Brazil Brazil Brazil Brazil Brazil Brazil Amazonia Amazonia Brazil Leaf is used in treating TB Leaves, stem bark and roots are used to treat coughs and TB Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Tea is indicated for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Tea and syrup are indicated for the treatment of lung problems, cough and TB Shoots are used to treat TB and cold South Pacific South Pacific Brazil Brazil Brazil Brazil Brazil Mexico (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Storey and Salem, 1997) (Storey and Salem, 1997; Leitão et al., 2013) (WHO, 1998) (WHO, 1998) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Leitão et al., 2013) (Coronado-Aceves et al., 2016) Used in the treatment of TB-related symptoms Used in the treatment of TB-related symptoms 2 dry pods in 1 L water as infusion/tea, daily dosage ad libitum Syrup are indicated for the treatment of lung problems, cough and TB Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Treatment of TB, pulmonary diseases or symptoms of these disorders Stem bark is used to prepare a remedy against cough which is also used for TB. Leaves are used in treating cough, sore throat and open wounds In the Solomon Islands, parts of the plant are used in treating cuts, TB and conjunctivitis. In New Guinea, the bark is used to make a cough remedy which is also used for TB Syrup is indicated for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms Leaves are used to treat TB, bronchitis and cough Leaves are used to treat bronchitis and TB. Stem bark infusion is used to treat TB and digestive tract problems. Tea is indicated for the treatment of lung problems, cough and TB Amazonia Amazonia Amazonia Brazil Brazil Amazonia South Pacific (Storey and Salem, 1997) (Storey and Salem, 1997) (Storey and Salem, 1997) (Leitão et al., 2013) (Leitão et al., 2013) (Storey and Salem, 1997) (WHO, 1998) Brazil Amazonia Mexico South Pacific (Leitão et al., 2013) (Storey and Salem, 1997) (Coronado-Aceves et al., 2016) (WHO, 1998) Brazil (Leitão et al., 2013) (continued on next page) Asphodelaceae Barringtoniaceae Bignoniaceae Brassicaceae Combretaceae Compositae 11 Crassulaceae Euphorbiaceae Goodeniaceae Lamiaceae Leguminosae (Fabaceae) Loranthaceae Lythraceae Malvaceae Meliaceae Myrtaceae Barringtonia asiatica (L.) Kurz Arrabidaea chica (H.B.K.) Verlot. Nasturtium officinale R. Br Terminalia catappa L. Artemisia spp. Bidens pilosa L. Elephantopus mollis Kunth. Heterocondylus alatus (Vell.) R.M.King and H.Rob. Hypochaeris brasiliensis (Less.) Hook. and Arn. Mikania laevigata Sch. Bip. ex Baker Solidago chilensis Meyen Vernonia phaeoneura Toledo Vernonia polyanthes Less. Vernonia westiniana Less. Vernonia spp. Spilanthes acmella (L.) L. Kalanchoe brasiliensis Cambess. Euphorbia fidjiana Boiss. Scaevola taccada (Gaertner) Roxb. Mentha pulegium L. Mentha x piperita L. Ocimum campechianum Mill. Ocimum gratissimum L. Hymenaea spp. Acacia cochliacantha Humb. & Bonpl. ex Willd. Bowdichia virgilioides Η.Β.Κ. Hymenaea courbaril L. Caesalpinia ferrea Mart. Struthanthus concinnus Mart. Struthanthus marginatus (Desr.) G. Don Punica granatum L. Hibiscus tiliaceus L. var. tiliaceus Malva spp. Carapa guianensis Aubl. Eucalyptus camaldulensis Dehnh. Syzygium malaccense (L.) Merr. & Perry Eugenia uniflora L. Biotechnology Advances xxx (xxxx) xxx–xxx Plant family J. Sharifi-Rad et al. Table 3 Medicinal plants used against tuberculosis in Americas. Biotechnology Advances xxx (xxxx) xxx–xxx (Storey and Salem, 1997) 2.4. Medicinal plants used in South Pacific and American traditional medicine for the management of tuberculosis Amazonia (WHO, 1998) (Storey and Salem, 1997) (Leitão et al., 2013) (Storey and Salem, 1997) (WHO, 1998) (WHO, 1998) (Leitão et al., 2013) (WHO, 1998) (WHO, 1998) South Pacific Amazonia Brazil Amazonia South Pacific South Pacific Brazil South Pacific South Pacific species have been recorded, belonging to 44 plant families. The most represented families are Leguminosae (or Fabaceae, 8 species), Lamiaceae (6 species) and Compositae (4 species) (Table 2). The most cited species are Adhatoda vasica (5 occurences), Tinospora cordifolia (3 occurences), Allium sativum, Acalypha indica, Asparagus racemosus, Cedrus deodara, Pinus contorta, Piper longum, Rubus occidentalis, Aloe vera, Glycyrrhiza glabra, Vitex negundo and Vitex trifolia (2 occurences) (Table 2). Adhatoda vasica oil from leaves, roots and flowers significantly inhibited the growth of M. tuberculosis B19-4 at a concentration of 4 μg/mL (Gautam et al., 2012). As well, the anti-TB activity of Tinospora cordifolia, Allium sativum, Acalypha indica, Aloe vera, Vitex negundo and Vitex trifolia have been documented (Arya, 2011). From American traditional medicine, which, in some cases, is a mixture of African and Asian knowledges, we recorded 52 plant species, belonging to 27 families, used to treat TB and related symptoms (Table 3). The most represented families are Compositae (12 species), Leguminosae (or Fabaceae, 5 species) and Lamiaceae (4 species) (Table 3). Most cited species is Chenopodium ambrosiodes L., whose antiTB activity has been reported previously (Ahmad et al., 2006). To summarize, most of plant species belongs to Leguminosae (Fabaceae) and Compositae families. Among all the identified species, only few are shared across continents. Allium cepa, Allium sativum, Aloe vera, Azadirachta indica, Lantana camara, Centella asiatica and Withania somnifera were recorded in Asia and Africa (Fig. 1). On the other hand, Bidens pilosa, Capsicum frutescens, Chenopodium ambrosiodes, Hibiscus tiliaceus, Cymbopogon citratus and Zingiber officinale were recorded in South Pacific-Americas and Africa, while only Morinda citrifolia was identified both in Asia and South Pacific-Americas (Fig. 1). In general, very little uniformity has been observed in the plants mentioned, highlighting the low consensus regarding TB remedies among the different traditional healing systems. This is likely due to the poor experimentation or evidence of efficacy for TB treatment, as well as the limited availability and accessibility of some endangered medicinal species. Zingiber officinale Roscoe. Zingiberaceae Solanaceae Urticaceae Bischofia javanica Blume Potomorphe peltata (L) Miq. Cymbopogon citratus (DC.) Stapf Ampelozizyphus amazonicus Ducke. Morinda citrifolia L. Citrus limon (L.) Osbeck Citrus aurantium L. Capsicum frutescens L. Dendrocnide harveyi (Seemann) Chew Orbiaceae Piperaceae Poaceae Rhamnaceae Rubiaceae Rutaceae The cambium of the plant is used to treat TB Used in the treatment of TB-related symptoms Tea, juice and syrup are indicated for the treatment of lung problems, cough and TB Used in the treatment of TB-related symptoms Liquid pressed from young fruit is used in the treatment of TB. Used for the treatment of TB, pulmonary disease or symptoms of these diseases Indicated for the treatment of lung problems, cough and TB Used as a remedy for TB A preparation made from scrapings of the stem bark is used in treating illnesses described as pain in the lungs with vomiting of blood (TB) Used in the treatment of TB-related symptoms References Botanical name Plant family Table 3 (continued) Mode of preparation/administration Locations J. Sharifi-Rad et al. 3. Targeting multidrug resistance in tuberculosis: management with phytochemicals and medicinal plants 3.1. Impact of MDR- and XDR-TB on public health Despite significant advances in treating the disease, tuberculosis continues to be a serious global health threat, with over 10.4 million cases, and 1.8 million deaths reported in 2015 (Smith et al., 2004; WHO, 2015; Nguyen, 2016; WHO, 2016). Mycobacterium tuberculosis (MTb), the etiologic agent of tuberculosis, is now considered one of the most successful pathogens among those causing infectious diseases, and the incidence of MTb infections is on the rise globally due, in part, to the advent of HIV/AIDS. The continued prevalence of MTb is due to the fact that this pathogen has an innate ability to survive host defense mechanisms, as well as the lack of new therapies, the inappropriate use of anti-TB drugs, disease states that complicate treatment such as diabetes mellitus and HIV, as well as the emergence of multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains (WHO, 2015). Over the last two decades, there has been a focus on the research and development of novel therapies for TB and several drugs have been evaluated in clinical trials (WHO, 2016). However, the number of effective drugs for TB is still very small, and treatment is complicated and very lengthy, leading to patient non-compliance and an increase in drug resistance. Over the past 40 years, the resistance of MTb has moved from mono-drug to multidrug resistance (MDR), extensively drug resistant (XDR), and eventually totally drug resistant (TDR), through 12 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. derivative, 130-bromotiliacorinine, were active against MDR-TB strains. The 59 strains of M. tuberculosis included 12 isolates resistant to isoniazid (INH) and rifampin (RMP); five isolates resistant to INH, RMP, and ethambutol (EMB); 23 isolates resistant to INH, RMP, and streptomycin (SM); nine isolates resistant to INH, RMP, EMB, and SM; one isolate resistant to INH, RMP, EMB, and ofloxacin (OFX); one isolate resistant to INH, RMP, SM, and OFX; and eight isolates resistant to INH, RMP, EMB, SM, and OFX. The results of this study showed that tiliacorinine, 20-nortiliacorinine, tiliacorine, and 130-bromotiliacorinine were active against MDR-MTB strains with median inhibitory concentration (MIC)s ranging from 0.7 to 6.2 μg/mL. Cytotoxicity in normal MRC-5 (human fetal lung fibroblast) cell line was also determined. The alkaloids were cytotoxic in this cell line with median inhibitory concentration (IC50) of 3.13–20.0 μg/mL (Sureram et al., 2012). Fig. 1. Distribution of medicinal plants identified in the traditional treatment of tuberculosis across continents. 3.4. Cinnamic acid derivatives In a 2011 study by Lakshmanan et al. (2011) a compound isolated from the rhizomes of Kaempferia galanga and identified as ethyl pmethoxycinnamate (EPMC) was tested against MTb strains. Antimycobacterial activity of EPMC was evaluated in MTb strains H37Ra (ATCC 25177) and H37Rv (ATCC 25618). Eight MTb clinical isolates, six of which from patients with MDR-TB, were obtained from the Swedish National Strain Collection at the Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden. The results of this study showed that EPMC inhibited the growth of all MTb strains tested, with a MIC of 0.485 mM. Four strains, irrespective of their drug resistance profiles (fully susceptible or MDR), were inhibited at 0.242 mM. EPMC toxicity was also tested on the human macrophage cell line THP-1 cells. An IC50 value of 3.8 mM was reported, indicating that EPMC was not toxic to macrophage cells at concentrations that could inhibit M. tuberculosis (Lakshmanan et al., 2011). Interestingly, the study also showed that the MDR strains did not exhibit higher MIC value than the susceptible ones, suggesting that the mechanism of action may be different from the target of any of the current anti-TB drugs (Lakshmanan et al., 2011). sequential accumulation of resistance mutations as reported by Nguyen (2016). MDR-TB strains are resistant to both isoniazid and rifampicin, and these strains were responsible for over 480,000 reported cases and approximately 210,000 deaths in 2013 (Nguyen, 2016). Extensively drug-resistant (XDR) MTb strains are also resistant to the quinolones and other second-line drugs and have been reported in at least 100 countries (WHO, 2015). The morbidity of XDR is 40–50% and poses a serious public health threat, especially in areas with high HIV prevalence. Antibiotic resistance of MTb strains continues to be a serious global health threat as some clinical strains have developed the means to evade all available antibiotics (Adhvaryu and Vakharia, 2011; Mishra et al., 2015; WHO, 2016). As a consequence, there is an urgent need to develop novel antituberculosis agents, particularly adjunct treatments that may be used to reverse antibiotic resistance, treat MDR- and XDR-TB, and to enhance the immune system to improve MTb recovery rates. In addition, most of the anti-TB drugs currently target metabolic reactions and proteins that are critical for the proliferation of M. tuberculosis (Adhvaryu and Vakharia, 2011). Future studies should focus on research and development of new drugs based on novel molecular targets related to the establishment of mycobacterial dormancy in human macrophages or inhibition of bacterial virulence factors that interfere with the signaling pathways of host cells and affect immunity, leading to the persistence of the disease (Koul et al., 2011). 3.5. Fungal metabolites Ganihigama et al. (2015) evaluated the anti-MTb activity of 27 naturally occurring compounds from fungi against MDR-TB isolates. Many of these natural products included anthraquinones, diterpenoids, alkaloids and flavonoids. The fungal metabolites were tested against a non-virulent H37Ra strain of M. tuberculosis and showed MIC values ranging from 3.1 μg/mL to > 100 μg/mL. Among the compounds tested, vermelhotin exhibited activity with MIC of 3.1 mg/mL (Ganihigama et al., 2015). Vermelhotin, a tetramic acid isolated from an unidentified marine fungus (CRI247–01) demonstrated antimycobacterial activity towards five reference strains (MIC 3.1–6.2 μg/ mL) and exhibited activity against the MDR-TB strains with MIC ranging between 1.5 μg/mL and 12.5 μg/mL (Ganihigama et al., 2015). Unfortunately, this compound was also cytotoxic in normal cells, MRC5 cell line (human lung fibroblast cells), with IC50 value of 6.97 μg/mL. 3.2. Natural products for MDR- and XDR-TB Medicinal plants have been used since the beginning of time to treat all diseases, including infectious diseases, and have been excellent leads for the development of new drugs. In fact, over the past 25 years, almost 50% of new drugs reviewed and approved by the US Food and Drug Administration have been derivatives of natural products (Newman and Cragg, 2007; Kinghorn et al., 2011; Cragg and Newman, 2013; Atanasov et al., 2015). Reviews of recently published scientific literature show that there are > 350 species of plants used for the treatment of TB, from countries around the world, and many naturally occurring compounds have been isolated and identified with activity against MTb, MDR-TB and XDR-TB (Camacho-Corona et al., 2008; Samad et al., 2008). The following is an overview of some of the classes of natural products showing some promising activity against MDR- and XDR-TB. 3.6. Iridoids Plants used in the Ayurvedic system of medicine containing iridoids, terpenes and other compounds have been shown to exert anti-MTb activities (Kumar et al., 2013). In one study on tree bark from Plumeria bicolor, a plant from India commonly known as Champa, several iridoids have been isolated and identified (Kumar et al., 2013). A methanol extract of the dried bark of P. bicolor, plumericin and isoplumericin were tested against susceptible MTb and four MDR-TB strains (Kumar et al., 2013).The extract showed a MIC between 20 and 25 μg/mL for all strains tested. Plumericin was very active against all 3.3. Bisbenzylisoquinolone alkaloids In a study by Sureram et al. (2012) bisbenzylisoquinoline alkaloids including tiliacorinine, 20-nortiliacorinine and tiliacorine isolated from roots of the edible plant Tiliacora triandra, as well as one synthetic 13 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. strains with a MIC between 1.3 and 2.1 μg/mL, with higher activity against the MDR strains. Isoplumericin was also active with MICs between 2.0 and 2.6 μg/mL for all strains tested. No cytotoxicity was reported for other cell lines. 3.9. Quinones and terpenes In 2016, Jyoti et al. reported the effects of an extract of Artemisia capillaris on the in vitro susceptibility of MTb. This plant is native to Central and Southeast Asia, particularly Korea, and is used as an antimicrobial agent. Two compounds from this extract were identified as active against MTb strains using bioassay-guided fractionation, ursolic acid (UA) and hydroquinone (HQ), with a MIC of 12.5 μg/mL against the susceptible strains, and of 12.5–25 μg/mL against MDR/XDR strains. This group also investigated the mechanism by which UA may exert its anti-MTb activity (Jyoti et al., 2016). In strain MTb H37Ra, UA decreased mycolic acid biosynthesis in a dose-dependent manner as determined by quantitative LC/MS/MS. This compound is a branched long-chain fatty acid that makes up to 60% of the outer cell wall of Mycobacterium. By inhibiting biosynthesis of mycolytic acid the bacterial cell wall cannot be formed and this causes Mycobacterium cell death. Electron microscopy further confirmed that UA had effects on both the cell wall and the intracellular content of H37Ra (Jyoti et al., 2015). In 2013, Metha et al. showed that extracts of Citrullus colocynthis (L.) Schrad. (Cucurbitaceae), known commonly as bitter apple, a medicinal plant from India used to treat bacterial infections, including tuberculosis and other respiratory diseases, had activity against MTb (Mehta et al., 2013). In this study, a methanol extract of the ripe fruits exhibited activity against MTb strains with a MIC ≤ 62.5 μg/mL. One fraction (FC III) of this extract showed a MIC of 31.2 μg/mL against strain MTb H37Rv, and other fractions also inhibited 16 clinical isolates of MTb, including 7 wild type, 8 MDR-TB, 1 XTB and 2 non-TB Mycobacterium strains with MICs in the range of 50–125, 31.2–125 and 62.5–125 μg/mL, respectively. Interestingly, the active compound identified from fraction FC III was UA, though other terpenes were also identified as cucurbitacin E 2-O-β-D-glucopyranoside and cucurbitacin I 2-O-β-D-glucopyranoside from fraction FC IX. Ursolic acid and cucurbitacin E 2-O-β-D-glucopyranoside were identified as the main chemical constituents active against MTb H37Rv (MICs 50 and 25 μg/mL, respectively), as well as against the clinical isolates (Mehta et al., 2013). In a publication by Uc-Cachón et al. (2014), naphthoquinones with anti-MTb activity were isolated from Diospyros anisandra, a native plant from the Yucatan peninsula used in traditional Mayan medicine. These compounds have a naphthalene skeleton substituted by ketone groups in positions C1 and C2 (1,2-naphthoquinones) or positions C1 and C4 (1,4-naphthoquinones), and are found as monomers, dimers, trimers or tetramers (Uc-Cachón et al., 2014). Naphthoquinones have a wide variety of biological activities, including antibacterial, antifungal, antiparasitic, antiviral, antiinflammatory and cytotoxic effects. In this study, stem bark extracts of Diospyros anisandra were active against MTb strains, and 3 monomeric and 5 dimeric naphthoquinones were isolated, identified and tested. Plumbagin and its dimers maritinone and 3,30-biplumbagin showed the highest activity against both susceptible and MDR-TB strains with a MIC of 1.56–3.33 mg/mL. Only maritinone and 3,30-biplumbagin showed no toxicity against normal eukaryotic cells, and had 32 times more activity against MDR-TB strains. In terms of mechanism of action, it has been shown that naphthoquinones can target the electron transport chain of Mycobacterium because they are structurally similar to menaquinone. In addition, they also may inhibit menaquinone biosynthesis thereby interfering with electron transport and cellular respiration (Uc-Cachón et al., 2013). 3.7. Marine natural products New interesting marine natural products have also been discovered with relevant activity against MTb and MDR-TB. From marine Streptomyces spp., cyclomarin A, a novel anti-inflammatory cyclic peptide, was isolated and showed high activity against MTb with MIC of 0.3 μg/mL (Lee and Suh, 2016). The MIC90 of the drug was 2.5 μM after 5 days of treatment, suggesting a high efficacy within short treatment times. The occurrence of anti-mycobacterial metabolites from marine invertebrates, namely sponges, corals and gorgonians has been recently investigated (Daletos et al., 2016; Sansinenea and Ortiz, 2016). The compound (−)-8,15-diisocyano-11(20)-amphilectene, a diterpene isolated from the Carribean sponge Svenzea flava, showed a promising activity with MIC value of 3.2 μg/mL; the calculated selectivity index (SI; i.e., IC50/MIC) of compound was equal to 10.2, suggesting that amphilectane-type diterpenes are important anti-tuberculosis pharmacophores (Nieves et al., 2016). Agelasines, purine diterpenes isolated from Agelasidae (Agelas spp.) marine sponges, were found to exhibit biological activity against the dormant state of MTb, which plays an important role in latent tuberculosis infection (Arai et al., 2014). Very recently, three haliclocyclamines, dimeric 3-alkyl piridinium alkaloids isolated from the Indonesian marine sponge Haliclona spp., showed a dose-dependent anti-mycobacterial activity, with the highest inhibition zone (10 mm) at 5 μg/disc (Maarisit et al., 2017). 3.8. Peptides Anti-mycobacterial peptides have been recently reviewed (Silva et al., 2016; Dong et al., 2017), though they have been investigating since many decades. In the 1960's, a cyclic peptide named griselimycin (GM) was discovered from Streptomyces spp.; it was effective against MTb, though its pharmacokinetic properties were poor (Holzgrabe, 2015). In 2015, Rolf Müller and colleagues retested GM after they increased the metabolic stability of the peptide by alkylating a proline residue in position 8. A novel metabolically stable cyclohexyl derivative was obtained with improved penetration of the mycobacterial cell wall, with a MIC of 0.06 μg/mL. The activity against MDR-TB was similar. Investigation on the mechanism of action showed that there was an amplification of the dnaN gene. This gene encodes for DnaN, a DNA polymerase sliding clamp that anchors the DNA to DNA polymerase, thus enhancing the replicatory strength of the enzyme and accelerating DNA replication and repair in prokaryotes. DnaN is a molecular target of GM, and GM derivatives appear to bind to a hydrophobic pocket of the DNA polymerase sliding clamp, making it an extremely novel mechanism of action (Lee and Suh, 2016). Lassomycin, a peptide composed of 16 amino acids, was identified from Lentzea kentuckyensis IO0009804, another actinomycete. This peptide had activity against MDR and XDR MTb, with MICs ranging from 0.41 to 1.65 μM (Lee and Suh, 2016). Another peptide named ecumicin, produced by Nonomuraea spp. MJM5123 and composed of 13 amino acids, also showed promising anti-TB activity against MDR and XDR MTb, with MIC values ranging from 0.16 to 0.62 μM. The minimal bactericidal concentration (MBC) was 1.5 μM (Lee and Suh, 2016). Sansanmycins are members of uridylpeptide family produced by the soil bacterium Streptomyces spp. These uridylpeptides are potents and selective anti-mycobacterials involved in inhibition of peptidoglycan biosynthesis (Tran et al., 2017). Teixobactin is a recently discovered anti-mycobacterial peptide isolated from Eleftheria terrae, a soil microorganism. The mechanism of action was identified as inhibition of peptidoglycan biosynthesis, though, noteworthy, teixobactin-resistant strains of M. tuberculosis could not be generated (Ling et al., 2015). 4. Case study: traditional Chinese medicine In traditional Chinese medicine (TCM), many herbal formulas have been used as adjunctive therapy, along with conventional TB chemotherapy, to manage MDR-TB. Some clinical trials have shown that various TCM herbal formulas can enhance the immune system, reduce adverse events observed with conventional TB chemotherapy, improve the overall quality of life, and decrease the level of MTb in sputum 14 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. culture (Jiang et al., 2015). One systematic review and meta-analysis analyzed 20 clinical trials involving 1823 TB patients from China (Jiang et al., 2015). This review concluded that adjunct therapy with TCM herbal formulas and TB chemotherapy significantly (p < 0.001) enhanced the treatment success and improved radiological findings. However, subjects who received TCM herbals in combination with chemotherapy had similar relapse rates; though the incidence of adverse events was lower (Jiang et al., 2015). These data suggest that TCM herbal medicines may improve the overall treatment and recovery of TB. A second systematic review and meta-analysis assessed the effects of TCMs in combination with TB chemotherapy in 30 randomized clinical trials (RCTs) involving 3374 participants with a diagnosis of MDR-TB (Wang et al., 2015). This review concluded that the quality of the clinical trials in the analysis was generally poor in terms of risk of bias. It further suggested again that TCM plus chemotherapy was more effective on the conversion rate of sputum as compared with chemotherapy alone. The study showed that, when compared with chemotherapy only, a benefit in MDR-TB patients was observed on the rate of reduction of lung lesions (in 7 studies), cavity closure rate (5 studies), reduced relapse rate (4 studies) and reduced abnormal liver function tests (14 studies) when TCM plus chemotherapy was used. No serious adverse event was reported in any of the study. The authors further suggested that, considering the positive results, further robust clinical trials are warranted (Wang et al., 2015). Beyond the clinical trials, one rodent study by Lu et al. (2013) investigated the effects of the traditional Chinese herbal medicines Radix Ranunculi Ternati, Radix Sophorae Flavescentis, Prunella vulgaris L. and Stellera chamaejasme L. on immunity in a rat model of MDR-TB. Treatment of the animals with the TCM herbal remedies significantly changed the levels of serum IFN-γ (p < 0.05). RT-PCR analysis showed a statistically significant increase in the mRNA levels of IFN-γ and IL-12, and a significant decrease in the mRNA levels of IL-4 and IL-10 (p < 0.05). In summary, this study showed that treatment with TCM herbs increased cellular-mediated immunity in a MDR-TB rodent model (Lu et al., 2013). In addition, an in vitro study performed by Nam et al. showed that (−)-deoxypergularine (DPX), an alkaloid extracted from the dried roots of the plant Cynanchum atratum (known as Bai Wei in TCM) showed activity against MDR-TB (Nam et al., 2016). The compound inhibited the growth of both susceptible and MDR-TB strains with a MIC of 12.5 μg/mL, with excellent activity against XDR-TB at 12.5 μg/mL. In a checkerboard assay, the combination of DPX and rifampin was synergistic in the MTb strain H37Ra, as was isoniazid plus DXP. In combination with streptomycin or ethambutol, the results were equivocal. Unfortunately, no checkerboard assays were performed on the XDRresistant strains (Nam et al., 2016). pathogen (Dini et al., 2011). In the last decades, the studies have focused to the efficacy of phytochemicals against multi-drug resistant isolates of Mycobacterium tuberculosis, thus providing promising results on the effectiveness of plant products against Mycobacterium. Garlic was demonstrated to possess antimycobacterial activity in many studies, where allicin was confirmed to be the carrier of this activity in the study of Gupta and Viswanathan (Gupta and Viswanathan, 1955). They found that this compound acts in synergistic manner with antibiotics streptomycin and chloramphenicol against M. tuberculosis. The same synergism was not detected when antitubercular drugs were combined with garlic extract, thus pointing to the allicin efficacy (Abbruzzese et al., 1987). Further studies on this subject confirmed garlic efficiency against various MTb strains, including MDR ones (Delaha and Garagusi, 1985; Ratnakar and Murthy, 1996; Gupta et al., 2010; Hannan et al., 2011). The most recent study of (Rajani et al., 2015), who investigated ethanol extract of garlic against 48 MDR and one reference strains (H37Rv) of MTb showed MIC values in the range of 0.5–2.0 mg/mL. Another plant of the Allium genus, shallot (Allium ascalonicum L.), was investigated for activity against MTb in the study of (Mansour et al., 2009). Its ethyl acetate extract exhibited activity against all of the ten tested clinical isolates of MTb at concentration of 500 μg/mL. Nine plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases were used for making hexane, methanol, chloroform and water extracts, which were further evaluated for antimycobacterial activity (Camacho-Corona et al., 2008). Among the tested extracts, the activity was shown by hexane (Citrus aurantifolia, C. sinensis, Foeniculum vulgare, Olea europaea), two chloroform (Larrea tridentata, Nasturtium officinale) and one methanol (Musa acuminata) extracts. Nasturtium officinale chloroform extract exhibited the most prominent activity against both reference and MDR strains (MICs were 100 μg/mL and < 100 μg/mL, respectively). Other extracts showing activity against these strains were Foeniculum vulgare and Olea europaea hexane extracts, which exhibited efficacy against all the resistant MTb variants at concentrations lower than 100 μg/mL. Study by León-Díaz et al. (2010) showed that hexane extract of Aristolochia taliscana, the herb used in Mexican traditional medicine, presents an important source of antimycobacterial compounds. This extract was tested against a wide range of mycobacteria including standard strain (H37Rv), four mono-resistant H37Rv variants and 12 clinical MDR isolates, as well as against five non-tuberculous mycobacteria. Bioguided fractionation of the obtained extract led to the isolation of the neolignans licarin A, licarin B and eupomatenoid-7, which all demonstrated antimycobacterial activity at very low concentrations (3.25–50.00 μg/mL). Among them, the most prominent action was observed for licarin A, which was active at 6.25 μg/mL even against MDR isolate resistant to first- and second-line antibiotics (LeónDíaz et al., 2010). Gupta et al. (2010) investigated activity of aqueous extracts of Acalypha indica and Adhatoda vasica leaves, bulbs of Allium cepa, cloves of Allium sativum and pure gel of Aloe vera leaves against MDR strains of MTb. All extracts were be effective against MDR isolates and drug-susceptible reference strain H37Rv. Among the tested acetone, ethanol and aqueous extracts obtained from 5 plants (Acorus calamus L. rhizome, Andrographis paniculata Nees. leaves, Ocimum sanctum L. leaves, Piper nigrum L. seeds and Pueraria tuberosa DC. tuber), only P. nigrum acetone extract showed to possess antimycobacterial activity (Birdi et al., 2012). In the study of Antony et al. (2012), butanol extracts of Alstonia scholaris fruits, flowers, bark and leaves were tested for efficacy against one standard strain (H37Rv), one clinical isolate sensitive to antibiotics, and one MDR clinical strain. The results pointed to significant efficacy of bark and leaf extracts against MDR strain at 100 μg/mL, while at 500 μg/mL all extracts showed inhibitory action against all tested strains. Among them, the highest activity was reported for bark extract of Alstonia scholaris, which showed inhibition of 47.40, 51.46 and 73.09% against standard, clinical sensitive and clinical MDR strains, respectively. 4.1. In vitro evidence Tuberculosis or ‘the white plague’, as people named it due to high fatal rate, even today presents one of the leading cause of motality with 9 million cases of active TB and 1.3 million deaths occurring every year (Hussain et al., 2014). Significant factors such as specific cell wall composition, dormant cells, long lasting therapy and inproper use of the first- and second-line drugs are related to continously increasing incidence of the multi-drug resistant (MDR) strains. Therefore, modern science is in constant search for novel alternatives in treating this infectious disease, especially those from natural sources which may have shorter treatment regimes and be effective with fewer side-effects. In these investigations, researchers mostly rely on the data obtained from traditional medicine practitioners. One of the first known studies in this route was the efficacy of garlic as antitubercular therapy, carried out in 1912 by Dr. Minchin. He performed anti-TB treatments on his patients by an inhaler mask containing a sponge soaked in garlic juice and reported that, in certain individuals, the drug was active against the 15 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. Seven mangrove plants (Ceriops decandra, Aegiceras corniculatum, Excoecaria agollacha, Avicennia officinalis, Rhizophora mucronata, Suaeda monoica and Sesuvium portulacastrum) were collected and their hexane and methanol extracts were tested for antimycobacterial activity (Prabhu, 2014). The assys were carried against one standard, one clinical strain sensitive to drugs and one strain of Mycobacterium tuberculosis resistant to streptomycin, isoniazid, rifampicin and ethambutol. Hexane extracts of all plants failed to exert antimycobacterial activity, while methanol extracts of E. agollacha, followed by those extracted from A. corniculatum and A. officinalis exhibited significant activity at concentrations of 500 μg/mL. In another study, fresh leaves of Taxus baccata, Senna alata, Andrographis paniculata, Adhatoda vasica, Acalypha indica and Aloe vera were extracted with water (ratio 1:1) and investigated against three MTb strains, including one MDR strain (DKU-156). The results showed inhibition of the treated MDR strain by all tested extracts at concentrations 2, 4 and 6% (Bernaitis et al., 2013). Among the tested extracts, T. baccata showed the highest potency considering percentage of bacterial growth reduction on LJ (Lowenstein Jensen) agar. In the study of Deveci et al. (2013), a total of 57 isolates including 17 MDR strains were investigated for sensitivity to Ankaferd Blood Stopper®, a mixture of plant extracts prepared from Alpinia officinarum, Glycyrrhiza glabra, Thymus vulgaris, Urtica dioica and Vitis vinifera. The mixture showed very significant antimycobacterial activity, with inhibitory concentrations ranging from < 1.37 μg/mL to 21.88 μg/mL. Singh et al. (2013) investigated different solvent extracts of two plants, Urtica dioica and Cassia sophera, for antimycobacterial activity. They determined that the hexane extract of U. dioica and methanol extract of C. sophera possessed this activity. Further testing of semi-purified fractions of these two extracts showed significant inhibition of clinical MDR strains of MTb. Gupta et al. (2014) investigated antimycobacterial activity of Alpinia galanga (L.) Willd. under intracellular and in axenic (aerobic and anaerobic) conditions. Intracellular assay represented a model for investigating the activity of the extracts against non-replicating dormant bacilli, characterized by the switch from aerobic/microaerophilic to anaerobic respiratory pathways. Among the tested extracts (obtained by water, acetone and ethanol Soxhlet extraction), acetone and etanolic extracts were active in all tested conditions at low concentrations (25, 50 and 100 μg/mL). Recently, similar investigation (in axenic and intracelluler conditions) was carried out by Bhatter et al. (2016) who tested the efficacy of acetone, ethanol and aqueous extracts of four plant species (Acorus calamus L. rhizome, Ocimum sanctum L. leaves, Piper nigrum L. seeds and Pueraria tuberosa DC. tuber) against MTb H37Rv. Acetone extract of P. nigrum showed the highest antimycobacterial activity by inhibiting the tested strain in aerobic, microaerophilic and anaerobic conditions. Also, water extract of P. tuberosa showed significant activity under reduced oxygen conditions, which pointed to the importance of anaerobiosis for its efficacy. Antimycobacterial activity of aqueous extracts of selected Indonesian medicinal plants (Andrographis paniculata, Annona muricata, Centella asiatica, Pluchea indica and Rhoeo spathacea) was investigated in the study of Radji et al. (2015). Their results showed that Pluchea indica and Rhoeo spathacea ehxibited promising antimycobacterial activity against a MDR strain of Mycobacterium tuberculosis, by inhibiting its growth at concentrations of 2.5 and 5 mg/mL. Another recent study on the plant efficacy against mycobacteria was the one performed by Jahanpour et al., 2015. They tested antimycobacterial activity of the ethanol extract from six Iranian medicinal plants against six clinical isolates (2 of them were MDR). The results pointed to significant activity of Peganum harmala and Punica granatum extracts. Owing to the fact that the assay was carried out using disc diffusion method, high concentrations (100 and 200 mg/mL) were determined to be active. Considering sensitive isolates, the inhibition zones of the P. harmala extract at higher concentration corresponded to those obtained by rifampin and isoniazid. Another study showed the activity of methanol, ethyl acetate and n-hexane extracts from plant material of Euphorbia hirta, a medicinal plant used in India for the treatment of many respiratory disorders (asthma, cough and various acute/chronic respiratory infections). Among the tested extracts, ethyl acetate extract showed the highest activity against MTb H37Rv, with concentration of 500 μg/mL reducing microbial growth to 35.27% in comparison with the untreated, control value (Rajasekar et al., 2015). Finally, four clinical isolates including two MDR and two sensitive strains to rifampin and isoniazid were used to investigate the antimycobacterial activity of the Peganum harmala hydro-alcoholic seed extract. All tested strains, including the MDR ones, showed sensitivity to this extract (Davoodi et al., 2015). 5. Conclusions The urgent need for development of new drugs to reduce the global burden of TB has greatly stimulated the exploration of traditional knowledge as source of novel and effective phytotherapeutic agents. Worldwide, many plant species have been and continue to be used in various traditional healing systems, as well as marine organisms and fungi, thus representing a nearly unlimited source of active ingredients. Noteworthy, besides their antimycobacterial activity, natural products can be useful in adjuvant therapy to improve the efficacy of conventional antimycobacterial therapies, to decrease their adverse effects and to reverse mycobacterial multi drug-resistance, the latter an emerging and very critical topic because of the genetic plasticity and environmental adaptability of Mycobacterium. Probably, the wide use of some traditional herbal remedies in the treatment of tuberculosis may be indicative of their efficacy and, above all, safety. Not least, natural products can also be used as a template for the development of new scaffolds of drugs. In any case, crude natural product extracts are complex mixtures of hundreds of different compounds that may be synergistically active once administered. Therefore, discovery and development of new pure products involve isolation, purification and identification of target compounds from complex crude extracts is sometimes a major drawback in natural products research. Not least, even if some natural products have still been investigated in clinical trials, the validation of their efficacy and safety as antituberculosis agents is far from being reached, and, hence, according to an evidence-based approach, more high-level randomized clinical trials are urgently needed. References Abbruzzese, M.R., Delaha, E.C., Garagusi, V.F., 1987. Absence of antimycobacterial synergism between garlic extract and antituberculosis drugs. Diagn. Microbiol. Infect. Dis. 8 (2), 79–85. Adhvaryu, M., Vakharia, B., 2011. Drug-resistant tuberculosis: emerging treatment options. Clin. Pharm. 3, 51–67. Ahmad, I., Aqil, F., Owais, M., 2006. Modern Phytomedicine: Turning Medicinal Plants into Drugs. Wiley, USA. Ahmed, H.M., 2016. Ethnopharmacobotanical study on the medicinal plants used by herbalists in Sulaymaniyah Province, Kurdistan, Iraq. J. Ethnobiol. Ethnomed. 12, 8. Ahuja, S., Ahuja, S., Ahuja, U., 2015. Nirgundi (Vitex negundo) – Nature's gift to mankind. Asian Agrihist. 19, 5–32. Alvin, A., Miller, K.I., Neilan, B.A., 2014. Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds. Microbiol. Res. 169 (7–8), 483–495. Antony, M., James, J., Misra, C.S., Sagadevan, L.D.M., Veettil, A.T., Thankamani, V., 2012. Anti mycobacterial activity of the plant extracts of Alstonia scholaris. Int. J. Curr. Pharm. Res. 4, 40–422. Arai, M., Yamano, Y., Setiawan, A., Kobayashi, M., 2014. Identification of the target protein of agelasine D, a marine sponge diterpene alkaloid, as an anti-dormant mycobacterial substance. Chem. Bio. Chem. 15 (1), 117–123. Arya, V., 2011. A review on anti-tubercular plants. Int. J. Phar.Tech Res. 3 (2), 872–880. Atanasov, A.G., Waltenberger, B., Pferschy-Wenzig, E.M., Linder, T., Wawrosch, C., Uhrin, P., Temml, V., Wang, L., Schwaiger, S., Heiss, E.H., Rollinger, J.M., Schuster, D., Breuss, J.M., Bochkov, V., Mihovilovic, M.D., Kopp, B., Bauer, R., Dirsch, V.M., Stuppner, H., 2015. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol. Adv. 33 (8), 1582–1614. Ayyanar, M., Ignacimuthu, S., 2008. Medicinal uses and pharmacological actions of five commonly used Indian medicinal plants: a mini-review. Iran. J. Pharmacol. Ther. 7, 16 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. 107–114. Batugal, P.A., Kanniah, J., Young, L.S., Oliver, J.T., 2004. Medicinal Plants Research in Asia. Serdang, Selangor DE, Malaysia: International Plant Genetic Resources Institute – Regional Office for Asia, the Pacific and Oceania (IPGRI-APO). Bedi, R.S., 2005. Management of tuberculosis in special situations. Lung India 22, 138–141. Bernaitis, L., Shenoy, V.P., Ashok, M., Nath, M., Shenoy, R.P., 2013. Effects of selective medicinal plants against multi drug resistance Mycobacterium tuberculosis strains. Res. J. Pharm., Biol. Chem. Sci. 4 (3), 812–817. Bhatter, P.D., Gupta, P.D., Birdi, T.J., 2016. Activity of medicinal plant extracts on multiplication of Mycobacterium tuberculosis under reduced oxygen conditions using intracellular and axenic assays. Int. J. Microbiol. 2016, 8073079. Birdi, T., D'souza, D., Tolani, M., Daswani, P., Nair, V., Tetali, P., Toro, J.C., Hoffner, S., 2012. Assessment of the activity of selected Indian medicinal plants against Mycobacterium tuberculosis: a preliminary screening using the Microplate Alamar Blue Assay. Eur. J. Med. Plant. 2 (4), 308–323. Bunalema, L., 2010. Anti-mycobacterial Activity and Acute Toxicity of Erythrina abyssinica, Cryptolepis sanguinolenta and Solanum incanum. Makerere University Kampala, Uganda. Camacho-Corona, M.R., Ramírez-Cabrera, M.A., Santiago, O.G., Garza-González, E., Palacios, I.P., Luna-Herrera, J., 2008. Activity against drug resistant-tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Phytother. Res. 22 (1), 82–85. Cardona, P., Ruiz-Manzano, J., 2004. On the nature of Mycobacterium tuberculosis-latent bacilli. Eur. Respir. J. 24 (6), 1044–1051. Chandra, S., Rawat, D.S., 2015. Medicinal plants of the family Caryophyllaceae: a review of ethno-medicinal uses and pharmacological properties. Integr. Med. Res. 4 (3), 123–131. Chiang, C.Y., Centis, R., Migliori, G.B., 2010. Drug-resistant tuberculosis: past, present, future. Respirology 15 (3), 413–432. Coronado-Aceves, E.W., Sánchez-Escalante, J.J., López-Cervantes, J., Robles-Zepeda, R.E., Velázquez, C., Sánchez-Machado, D.I., Garibay-Escobar, A., 2016. Antimycobacterial activity of medicinal plants used by the Mayo people of Sonora, Mexico. J. Ethnopharmacol. 190, 106–115. Cragg, G.M., Newman, D.J., 2013. Natural products: a continuing source of novel drug leads. Biochim. Biophys. Acta 1830 (6), 3670–3695. Daletos, G., Ancheeva, E., Chaidir, C., Kalscheuer, R., Proksch, P., 2016. Antimycobacterial metabolites from marine invertebrates. Arch. Pharm. 349, 763–773. Davoodi, H., Ghaemi, E., Mazandarani, M., Shakeri, F., Javid, S., Klishadi, M., 2015. Antimycobacterial and anti-inflammatory activity of Peganum harmala. J. Chem. Pharm. Res. 7 (4), 1611–1616. Debnath, P.K., Chattopadhyay, J., Mitra, A., Adhikari, A., Alam, M.S., Bandopadhyay, S.K., Hazra, J., 2012. Adjunct therapy of Ayurvedic medicine with anti tubercular drugs on the therapeutic management of pulmonary tuberculosis. J. Ayurveda Integr. Med. 3 (3), 141–149. Delaha, E.C., Garagusi, V.F., 1985. Inhibition of mycobacteria by garlic extract (Allium sativum). Antimicrob. Agents Chemother. 27 (4), 485–486. Deveci, A., Coban, A.Y., Tanrıverdi, Ç.Y., Acicbe, O., Taşdelen, F.N., Akgüneş, A., Ozatlı, D., Uzun, M., Durupınar, B., 2013. In vitro effect of Ankaferd Blood Stopper®, a plant extract against Mycobacterium tuberculosis isolates. Mikrobiyol. Bul. 47 (1), 71–78. Dhanabal, S.P., Lall, N., Pavithra, N., Chaitanya, M.V.N.L., 2015. Natural products as an important leads for discovery of new antitubercular agents: a review. Int J Pharm Pharm Sci 7 (10), 2–7. Diacon, A.H., Pym, A., Grobusch, M., Patientia, R., Rustomjee, R., Page-Shipp, L., Pistorius, C., Krause, R., Bogoshi, M., Churchyard, G., Venter, A., Allen, J., Palomino, J.C., De Marez, T., Van Heeswijk, R.P., Lounis, N., Meyvisch, P., Verbeeck, J., Parys, W., De Beule, K., Andries, K., Mc Neeley, D.F., 2009. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med. 360 (23), 2397–2405. Dini, C., Fabbri, A., Geraci, A., 2011. The potential role of garlic (Allium sativum) against the multi-drug resistant tuberculosis pandemic: a review. Ann. Ist. Super. Sanita 47 (4), 465–473. Dong, M., Pfeiffer, B., Altmann, K.H., 2017. Recent developments in natural productbased drug discovery for tuberculosis. Drug Discov. Today 22 (3), 585–591. Faleyimu, O.I., Akinyemi, O., Adejoba, O.R., 2009. Herbal solution to the treatment of tuberculosis infection in Kaduna south local government, Kaduna, Nigeria. J. Environ. Ext. 8 (3), 40–43. Farshidpour, M., Ebrahimi, G., Mirsaeidi, M., 2013. Multidrug-resistant tuberculosis treatment with linezolid-containing regimen. Int. J. Mycobacteriol. 2 (4), 233–236. Ganihigama, D.U., Sureram, S., Sangher, S., Hongmanee, P., Aree, T., Mahidol, C., Ruchirawat, S., Kittakoop, P., 2015. Antimycobacterial activity of natural products and synthetic agents: pyrrolodiquinolines and vermelhotin as anti-tubercular leads against clinical multidrug resistant isolates of Mycobacterium tuberculosis. Eur. J. Med. Chem. 89, 1–12. Gautam, R., Saklani, A., Jachak, S.M., 2007. Indian medicinal plants as a source of antimycobacterial agents. J. Ethnopharmacol. 110 (2), 200–234. Gautam, H.A., Sharma, R., Rana, A.C., 2012. Review on herbal plants useful in tuberculosis. Int. Res. J. Pharm. 3 (7), 64–67. Ghanashyam, B., 2016. Changing the game for multidrug-resistant tuberculosis. Lancet 387 (10024), 1149–1150. Green, E., Samie, A., Obi, C.L., Bessong, P.O., Ndip, R.N., 2010. Inhibitory properties of selected South African medicinal plants against Mycobacterium tuberculosis. J. Ethnopharmacol. 130 (1), 151–157. Gupta, K., Viswanathan, R., 1955. Combined action of streptomycin and chloramphenicol with plant antibiotics against tubercle bacilli. Part I: streptomycin and chloramphenicol with cepharanthine. Part II: streptomycin and allicin. Antibiot. Chemother. 5 (1), 24–27. Gupta, R., Thakur, B., Singh, P., Singh, H.B., Sharma, V.D., Katoch, V.M., Chauhan, S.V., 2010. Anti-tuberculosis activity of selected medicinal plants against multi-drug resistant Mycobacterium tuberculosis isolates. Indian J. Med. Res. 131, 809–813. Gupta, P., Bhatter, P., D'souza, D., Tolani, M., Daswani, P., Tetali, P., Birdi, T., 2014. Evaluating the anti Mycobacterium tuberculosis activity of Alpinia galanga (L.) Willd. axenically under reducing oxygen conditions and in intracellular assays. BMC Complement. Altern. Med. 4 (14), 84. Hannan, A., Ikram Ullah, M., Usman, M., Hussain, S., Absar, M., Javed, K., 2011. Antimycobacterial activity of garlic (Allium sativum) against multi-drug resistant and nonmulti-drug resistant Mycobacterium tuberculosis. Pak. J. Pharm. Sci. 24, 81–85. Holtz, T., Cegielski, J., 2007. Origin of the term XDR-TB. Eur. Respir. J. 30 (2), 396. Holzgrabe, U., 2015. New griselimycins for treatment of tuberculosis. Chem. Biol. 22 (8), 981–982. Hussain, S., Haq, A., Nisar, M., Ahmad, T., Bhardwaj, P., 2014. Evaluation of in-vitro antimycobacterial activity and isolation of active constituents from Crocus sativus L. (Iridaceae). Asian J. Med. Pharma. Res. 4, 130–135. Jahanpour, S., Ghazisaidi, K., Davoodi, H., Mazandarani, M., Samet, M., Jahanpour, N., Ghaemi, E.A., 2015. Antimicrobial effects of folk medicinal plants from the north of Iran against Mycobacterium tuberculosis. Arch. Pediatr. Infect. Dis. 3 (1 TB), e18098. Jiang, R.H., Xu, H.B., Fu, J., 2015. Outcomes of Chinese herb medicine for the treatment of multidrug-resistant tuberculosis: a systematic review and meta-analysis. Complement. Ther. Med. 23 (4), 544–554. Jyoti, M.A., Zerin, T., Kim, T.H., Hwang, T.S., Jang, W.S., Nam, K.W., Song, H.Y., 2015. In vitro effect of ursolic acid on the inhibition of Mycobacterium tuberculosis and its cell wall mycolic acid. Pulm. Pharmacol. Ther. 33, 17–24. Jyoti, M.A., Nam, K.W., Jang, W.S., Kim, Y.H., Kim, S.K., Lee, B.E., Song, H.Y., 2016. Antimycobacterial activity of methanolic plant extract of Artemisia capillaris containing ursolic acid and hydroquinone against Mycobacterium tuberculosis. J. Infect. Chemother. 22 (4), 200–208. Kaufmann, S., Evans, T.G., Hanekom, W.A., 2015. Tuberculosis vaccines: time for a global strategy. Sci. Transl. Med. 7, 276fs8. Kinghorn, A.D., Pan, L., Fletcher, J.N., Chai, H., 2011. The relevance of higher plants in lead compound discovery programs. J. Nat. Prod. 74 (6), 1539–1555. Koul, A., Arnoult, E., Lounis, N., Guillemont, J., Andries, K., 2011. The challenge of new drug discovery for tuberculosis. Nature 469, 483–490. Kumar, P., Singh, A., Sharma, U., Singh, D., Dobhal, M., Singh, S., 2013. Anti-mycobacterial activity of plumericin and isoplumericin against MDR Mycobacterium tuberculosis. Pulm. Pharmacol. Ther. 26 (3), 332–335. Lakshmanan, D., Werngren, J., Jose, L., Suja, K.P., Nair, M.S., Varma, R.L., Mundayoor, S., Hoffner, S., Kumar, R.A., 2011. Ethyl p-methoxycinnamate isolated from a traditional anti-tuberculosis medicinal herb inhibits drug resistant strains of Mycobacterium tuberculosis in vitro. Fitoterapia 82 (5), 757–761. Lall, N., Meyer, J.J.M., 1999. In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants. J. Ethnopharmacol. 66 (3), 347–354. Lalvani, A., Sridhar, S., Von Reyn, C.F., 2013. Tuberculosis vaccines: time to reset the paradigm? Thorax 68 (12), 1092–1094. Lawal, I.O., Grierson, D.S., Afolayan, A.J., 2014. Phytotherapeutic information on plants used for the treatment of tuberculosis in eastern Cape Province, South Africa. Evid. Based Complement. Alternat. Med. 2014, 735423. Lee, H., Suh, J.W., 2016. Anti-tuberculosis lead molecules from natural products targeting Mycobacterium tuberculosis ClpC1. J. Ind. Microbiol. Biotechnol. 43 (2–3), 205–212. Lee, M., Cho, S.N., Barry 3rd, C.E., Song, T., Kim, Y., Jeong, I., 2015. Linezolid for XDRTB—final study outcomes. N. Engl. J. Med. 373 (3), 290–291. Leitão, F., Leitão, S.G., De Almeida, M.Z., Cantos, J., Coelho, T., Da Silva, P.E., 2013. Medicinal plants from open-air markets in the state of Rio de Janeiro Brazil as a potential source of new antimycobacterial agents. J. Ethnopharmacol. 149 (2), 513–521. León-Díaz, R., Meckes, M., Said-Fernández, S., Molina-Salinas, G.M., Vargas-Villarreal, J., Torres, J., Luna-Herrera, J., Jiménez-Arellanes, A., 2010. Antimycobacterial neolignans isolated from Aristolochia taliscana. Mem. Inst. Oswaldo Cruz 105 (1), 45–51. Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., Mueller, A., Schäberle, T.F., Hughes, D.E., Epstein, S., Jones, M., Lazarides, L., Steadman, V.A., Cohen, D.R., Felix, C.R., Fetterman, K.A., Millett, W.P., Nitti, A.G., Zullo, A.M., Chen, C., Lewis, K., 2015. A new antibiotic kills pathogens without detectable resistance. Nature 517 (7535), 455–459. Liu, Q., Garner, P., Wang, Y., Huang, B., Smith, H., 2008. Drugs and herbs given to prevent hepatotoxicity of tuberculosis therapy: systematic review of ingredients and evaluation studies. BMC Public Health 8, 365. Lu, J., Ye, S., Qin, R., Deng, Y., Li, C.P., 2013. Effect of Chinese herbal medicine extracts on cell-mediated immunity in a rat model of tuberculosis induced by multiple drugresistant bacilli. Mol. Med. Rep. 8 (1), 227–232. Maarisit, W., Abdjul, D.B., Yamazaki, H., Kato, H., Rotinsulu, H., Wewengkang, D.S., Sumilat, D.A., Kapojos, M.M., Ukai, K., Namikoshi, M., 2017. Anti-mycobacterial alkaloids, cyclic 3-alkyl pyridinium dimers, from the Indonesian marine sponge Haliclona sp. Bioorg. Med. Chem. Lett (pii: S0960-894X(17)30564-4). Madikizela, B., 2014. Pharmacological Evaluation of South African Medicinal Plants Used for Treating Tuberculosis and Related Symptoms South Africa: University of KwaZulu-Natal. Mangtani, P., Abubakar, I., Ariti, C., Beynon, R., Pimpin, L., Fine, P.E.M., Rodrigues, L.C., Smith, P.G., Lipman, M., Whiting, P.F., Sterne, J.A., 2014. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin. Infect. Dis. 58 (4), 470–480. Mansour, A., Sepideh, S., Mohammad, H., 2009. Antimycobacterial activity of partial purified extract of Allium ascalonicum. Jundishapur J. Microbiol. 2 (40), 144–147. 17 Biotechnology Advances xxx (xxxx) xxx–xxx J. Sharifi-Rad et al. partially purified proteins (Garlic defensins?). Indian J. Clin. Biochem. 11 (1), 37–41. Saganuwan, A.S., 2010. Some medicinal plants of Arabian Pennisula. Med. Plants Res. 4, 766–788. Samad, A., Sultana, Y., Akhter, M.S., Aqil, M., 2008. Treatment of tuberculosis: use of active pharmaceuticals. Recent Pat. Antiinfect. Drug Discov. 3, 34–44. Samal, J., 2016. Ayurvedic management of pulmonary tuberculosis: a systematic review. J. Intercult. Ethnopharmacol. 5 (1), 86–91. Sansinenea, E., Ortiz, A., 2016. Antimycobacterial natural products from marine Pseudopterogorgia elisabethae. Curr. Org. Synth. 13 (4), 556–568. Silva, J.P., Appelberg, R., Gama, F.M., 2016. Antimicrobial peptides as novel anti-tuberculosis therapeutics. Biotechnol. Adv. 34 (5), 924–940. Singh, R., Hussain, S., Verma, R., Sharma, P., 2013. Anti-mycobacterial screening of five Indian medicinal plants and partial purification of active extracts of Cassia sophera and Urtica dioica. Asian Pac J Trop Med 6 (5), 366–371. Smith, I., 2003. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin. Microbiol. Rev. 16 (3), 463–496. Smith, C.B., Battin, M.P., Jacobson, J.A., Francis, L.P., Botkin, J.R., Asplund, E.P., Domek, G.J., Hawkins, B., 2004. Are there characteristics of infectious diseases that raise special ethical issues? Dev. World Bioeth. 4 (1), 1–16. Storey, C., Salem, J.I., 1997. Lay use of amazonian plants for the treatment of tuberculosis. Acta Amaz 27 (3), 175–182. Sureram, S., Senadeera, S.P., Hongmanee, P., Mahidol, C., Ruchirawat, S., Kittakoop, P., 2012. Antimycobacterial activity of bisbenzylisoquinoline alkaloids from Tiliacora triandra against multidrug-resistant isolates of Mycobacterium tuberculosis. Bioorg. Med. Chem. Lett. 22 (8), 2902–2905. Tabuti, J.R.S., Kukunda, C.B., Waako, P.J., 2010. Medicinal plants used by traditional medicine practitioners in the treatment of tuberculosis and related ailments in Uganda. J. Ethnopharmacol. 127 (1), 130–136. Talavera, W., Miranda, R., Lessnau, K., Klapholz, A., 2001. Extrapulmonary tuberculosis. In: Tuberculosis: current concepts and treatment, 2nd ed. CRC Press, Inc, Boca Raton, Fla, pp. 139–190. Tascon, R., Soares, C., Ragno, S., Stavropoulos, E., Hirst, E., Colston, M., 2000. Mycobacterium tuberculosis-activated dendritic cells induce protective immunityin mice. Immunology 99 (3), 473–480. Tewari, U., Bahadur, A.N., Soni, P., 2015. Study of some ethno medicinal plants cultivated in botanical garden, science college, Bilaspur (C.G.). Int. J. Adv. Res. Biol. Sci. 2, 353–359. Tiemersma, E.W., Van der Werf, M.J., Borgdorff, M.W., Williams, B.G., Nagelkerke, N.J., 2011. Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One 6, e17601. Tran, A.T., Watson, E.E., Pujari, V., Conroy, T., Dowman, L.J., Giltrap, A.M., Pang, A., Wong, W.R., Linington, R.G., Mahapatra, S., Saunders, J., Charman, S.A., West, N.P., Bugg, T.D., Tod, J., Dowson, C.G., Roper, D.I., Crick, D.C., Britton, W.J., Payne, R.J., 2017. Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nat. Commun. 8, 14414. Uc-Cachón, A., Molina-Salinas, G., Said-Fernández, S., Méndez-González, M., CáceresFarfán, M., Borges-Argáez, R., 2013. A new dimeric naphthoquinone from Diospyros anisandra. Nat. Prod. Res. 27 (13), 1174–1178. Uc-Cachón, A.H., Borges-Argáez, R., Said-Fernández, S., Vargas-Villarreal, J., GonzálezSalazar, F., Méndez-González, M., Cáceres-Farfán, M., Molina-Salinas, G.M., 2014. Naphthoquinones isolated from Diospyros anisandra exhibit potent activity against pan-resistant first-line drugs Mycobacterium tuberculosis strains. Pulm. Pharmacol. Ther. 27 (1), 114–120. Velayati, A.A., Farnia, P., Masjedi, M.R., 2012. Letter to editor recurrence after treatment success in pulmonary multidrug-resistant tuberculosis: predication by continual PCR positivity. Int. J. Clin. Exp. Med. 5 (3), 271–272. Viswanathan, V., Phadatare, A.G., Mukne, A., 2014. Antimycobacterial and antibacterial activity of Allium sativum bulbs. Indian J. Pharm. Sci. 76 (3), 256–261. Wang, J.F., Dai, H.Q., Wei, Y.L., Zhu, H.J., Yan, Y.M., Wang, Y.H., Long, C.L., Zhong, H.M., Zhang, L.X., Cheng, Y.X., 2010. Antituberculosis agents and an inhibitor of the para-aminobenzoic acid biosynthetic pathway from hydnocarpus anthelminthica seeds. Chem. Biodivers. 7 (8), 046–053. Wang, M., Guan, X., Chi, Y., Robinson, N., Liu, J.P., 2015. Chinese herbal medicine as adjuvant treatment to chemotherapy for multidrug-resistant tuberculosis (MDR-TB): a systematic review of randomised clinical trials. Tuberculosis 95, 364–372. Warrier, P.K., 2002. Indian Medicinal Plants. Orient Longman, Hyderabad. Wayne, L.G., Sohaskey, C.D., 2001. Nonreplicating persistence of Mycobacterium tuberculosis. Annu. Rev. Microbiol. 55, 139–163. World Health Organization (WHO), 1998. Medicinal Plants in the South Pacific. World Health Organization, Regional Office for the Western Pacific in Manila, Philippines. World Health Organization (WHO), 2013. The Use of Bedaquiline in the Treatment of Multidrug-resistant Tuberculosis: Interim Policy Guidance. World Health Organization (WHO), 2015. Global Tuberculosis Report. World Health Organization (WHO), 2016. Global Tuberculosis Report. World Health Organizationpp. 2015. Zhang, L., Li, R., Li, M., Qi, Z., Tian, J., 2015. In vitro and in vivo study of anti-tuberculosis effect of extracts isolated from Ranunculi Ternati radix. Sarcoidosis Vasc. Diffuse. Lung Dis. 31 (4), 336–342. Mariita, M.A.R., 2006. Efficacy of Medicinal Plants Used by Communities around Lake Victoria Region and the Samburu against Mycobacteria, Selected Bacteria and Candida albicans Kenya: Kenyatta University. Masjedi, M.R., Farnia, P., Sorooch, S., Pooramiri, M.V., Mansoori, S.D., Zarifi, A.Z., Velayati, A.A., Hoffner, S., 2006. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin. Infect. Dis. 43 (7), 841–847. Masjedi, M., Tabarsi, P., Chitsaz, E., Baghaei, P., Mirsaeidi, M., Amiri, M.V., Farnia, P., Javanmard, P., Mansouri, D., Velayati, A.A., 2008. Outcome of treatment of MDR-TB patients with standardised regimens, Iran, 2002–2006. Int. J. Tuberc. Lung. Dis. 12 (7), 750–755. Masjedi, M.R., Tabarsi, P., Marjani, M., Shiva, P.B., Nasehi, M., Gooya, M.M., Farnia, P., Velayati, A.A., 2013. Management of MDR-TB: review of Iran's experience. Tanaffos 12 (1), 6–15. Mativandlela, S.P.N., Lall, N., Meyer, J.J.M., 2006. Antibacterial, antifungal and antitubercular activity of (the roots of) Pelargonium reniforme (CURT) and Pelargonium sidoides (DC) (Geraniaceae) root extracts. S. Afr. J. Bot. 72, 232–237. Mehta, P.K., King, C.H., White, E.H., Murtagh, J., Quinn, F.D., 1996. Comparison of in vitro models for the study of Mycobacterium tuberculosis invasion and intracellular replication. Infect. Immun. 64 (7), 2673–2679. Mehta, A., Srivastva, G., Kachhwaha, S., Sharma, M., Kothari, S., 2013. Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates. J. Ethnopharmacol. 149 (1), 195–200. Meyer, J.J.M., Lall, N., Mathekga, A.D.M., Jäger, A.K., 2002. In vitro inhibition of drugresistant and drug-sensitive strains of Mycobacterium tuberculosis by Helichrysum caespititium. S. Afr. J. Bot. 68 (1), 90–93. Millard, J., Ugarte-Gil, C., Moore, D.A., 2015. Multidrug resistant tuberculosis. BMJ 350, h882. Mishra, R., Shukla, P., Huang, W., Hu, N., 2015. Gene mutations in Mycobacterium tuberculosis: multidrug-resistant TB as an emerging global public health crisis. Tuberculosis (Edinb) 95 (1), 1–5. Mohamad, S., Zin, N.M., Wahab, H.A., Ibrahim, P., Sulaiman, S.F., Zahariluddin, A.S., Noor, S.S., 2011. Antituberculosis potential of some ethnobotanically selected Malaysian plants. J. Ethnopharmacol. 133 (3), 1021–1026. Nair, C.K.N., 1998. Medicinal Plants of India. Nag Publishers, New Delhi. Nam, K.W., Jang, W.S., Jyoti, M.A., Kim, S., Lee, B.E., Song, H.Y., 2016. In vitro activity of (-)-deoxypergularinine, on its own and in combination with anti-tubercular drugs, against resistant strains of Mycobacterium tuberculosis. Phytomedicine 23 (5), 578–582. Namita, P., Mukesh, R., 2012. Medicinal plants used as antimicrobial agents: review. Int. Res. J. Pharm. 3, 31–40. Newman, D.J., Cragg, G.M., 2007. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70 (3), 461–477. Nguta, J.M., Appiah-Opong, R., Nyarko, A.K., Yeboah-Manu, D., Addo, P.G.A., 2015. Medicinal plants used to treat TB in Ghana. Int. J. Mycobacteriol. 4 (2), 116–123. Nguyen, L., 2016. Antibiotic resistance mechanisms in M. tuberculosis: an update. Arch. Toxicol. 90 (7), 1585–1604. Nieves, K., Prudhomme, J., Le Roch, K.G., Franzblau, S.G., Rodríguez, A.D., 2016. Natural product-based synthesis of novel anti-infective isothiocyanate-and isoselenocyanatefunctionalized amphilectane diterpenes. Bioorg. Med. Chem. Lett. 26 (3), 854–857. Ofukwu, R.A., Ayoola, A., Akwuobu, C.A., 2008. Medicinal plants used in the treatment of tuberculosis in humans and animals by Idoma tribe of north-central Nigeria. Niger. Vet. J. 29 (2), 25–30. Ogbole, O.O., Ajaiyeoba, E.O., 2010. Traditional Management of Tuberculosis in Ogun State of Nigeria: the practice and ethnobotanical survey. Afr. J. Tradit. Complement. Altern. Med. 7 (1), 79–84. Orodho, J.A., Okemo, P., Otieno, N., Kirimuhuzya, C.M.J.J., 2014. Indigenous knowledge of communities around Lake Victoria Basin regarding treatment and management of tuberculosis using medicinal plants. Int. J. Med. Med. Sci. 6, 16–23. Parrish, N.M., Dick, J.D., Bishai, W.R., 1998. Mechanisms of latency in Mycobacterium tuberculosis. Trends Microbiol. 6 (3), 107–112. Paulson, T., 2013. Epidemiology: a mortal foe. Nature 502, S2–S3. Poonam, K., Singh, G.S., 2009. Ethnobotanical study of medicinal plants used by the Taungya community in Terai Arc Landscape, India. J. Ethnopharmacol. 123 (1), 167–176. Prabhu, A., 2014. Antimycobacterial activity of certain mangrove plants against multidrug resistant Mycobacterium tuberculosis. Asian J. Med Sci. 5 (3), 54–57. Radji, M., Kurniati, M., Kiranasari, A., 2015. Comparative antimycobacterial activity of some Indonesian medicinal plants against multi-drug resistant Mycobacterium tuberculosis. J. App. Pharm. Sci. 5 (1), 019–022. Rajani, S.D., Desai, P.B., Rajani, D.P., 2015. Anti-mycobacterial activity of garlic (Allium sativum) against multi-drug resistant and reference strain of Mycobacterium tuberculosis. Int. J. Appl. Res. 1 (13), 767–770. Rajasekar, T., Anbarasu, S., Manikkam, R., Joseph, J., Kumar, V., 2015. Inhibitory activity of Euphorbia hirta (Tawa-tawa) extracts against Mycobacterium tuberculosis and other non mycobacterial pathogens. Der Pharma Chemica 7 (8), 213–216. Ratnakar, P., Murthy, P.S., 1996. Preliminary studies on the antitubercular activity and the mechanism of action of the water extract of garlic (Allium sativum) and its two 18