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
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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
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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
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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