Ramadan 1

Received: 9 November 2020 Revised: 8 April 2021 Accepted: 13 April 2021
DOI: 10.1002/mco2.82
REVIEW
Advances in adjunct therapy against tuberculosis:

Deciphering the emerging role of phytochemicals
Samreen Fatima Anjna Kumari Ved Prakash Dwivedi
Immunobiology Group, International

Centre for Genetic Engineering and Abstract
Biotechnology, New Delhi, India Eastern countries are a major source of medicinal plants, which set up a rich
Correspondence
source of ethnopharmacologically known medicines used in the treatment of
Dr Ved Prakash Dwivedi, Immunobiology various diseases. These traditional medicines have been known as complemen-
Group, International Centre for Genetic tary, alternative, or nonconventional therapy across globe for ages. Tuberculo-
Engineering and Biotechnology, New
Delhi, India sis (TB) poses a huge global burden and leads to maximum number of deaths
Email: [email protected] due to an infectious agent. Treatment of TB using Directly Observed Treatment
Short-course (DOTS) therapy comprises multiple antibiotics is quite lengthy and
causes serious side-effects in different organs. The length of the TB treatment
leads to withdrawal from the patients, which paves the way for the emergence
of drug resistance in the bacterial population. These concerns related to therapy
need serious and immediate interventions. Traditional medicines using phyto-
chemicals has shown to provide tremendous potential in TB treatment, mainly in
the eradication of Mycobacterium tuberculosis (M.tb), increasing natural immu-
nity, and managing the side effects of anti-TB drugs. This review describes the
antituberculosis potential of selected ethnopharmacologically important phyto-
chemicals as potential immune-modulator and as an adjunct-therapy in TB. This
review will be a useful reference for researchers working on ethnopharmacology
and will open the door for the discovery of novel agents as an adjunct-therapy to
tuberculosis.
KEYWORDS
adjunct therapy, cytokines, immunomodulation, Mycobacterium tuberculosis, phytochemicals,
T cells
1 INTRODUCTION remains a threat with 10.5 million new cases reported

in 2019.1 WHO reports that there are documented 10.5
Tuberculosis (TB) is a communicable disease caused by million new cases of TB each year with almost 1.8 million
slow-growing, acid-fast bacillus Mycobacterium tuberculo- deaths. Needless to say that about one-third of the cases
sis (M. tuberculosis). BCG (Bacillus Calmette-Guérin) is the still remain unreported.2
only validated vaccine against pulmonary TB. However, M. tuberculosis is inhaled in the form of small aerosol
despite years of vaccination and antibiotic therapy, TB droplets containing the bacilli and is transmitted to healthy
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2021 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
494 wileyonlinelibrary.com/journal/mco2 MedComm. 2021;2:494–513.

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FATIMA et al. 495
FIGURE 1 Tuberculosis treatment and associated side effects
individual from an infected person through the respiratory opment of effective vaccine strategies and immune thera-
route via inhalation into the lungs. The bacteria travel peutics. M. tuberculosis infects the healthy individuals by
through the lungs and reside in the alveoli of the lungs. In getting inhaled in form of the bacilli containing aerosol
90% of the infected individuals, the infection does not lead droplets, which are released from an infected person. After
to active disease and is called a latent state of infection getting inhaled, the bacteria travel through the mucosal
where bacteria can live for many years in a nonreplicat- pathway and reach the alveoli of the lungs. The alveo-
ing state. In the remaining 10% individuals, who are in lar macrophages are the first cells that encounter these
immune-compromised state, the disease may take the pathogens and engulf them.6 These macrophages secrete
active replicating form.3 Treatment of TB is globally known cytokines and chemokines that recruit other inflammatory
as “Directly Observed Treatment Short-course (DOTS).” It cells to the site of infection. Alveolar macrophages together
is a multidrug and a long-term therapy. It consists of many with neutrophils and other inflammatory cells organize
antibiotics that cause severe toxicity and side effects.4,5 themselves into compact structures called granulomas.
After approximately 4 weeks of treatment with antibiotics, Granulomas form in the lungs to limit the growth of M.
the patient’s condition improves significantly, causing him tuberculosis. The macrophages and dendritic cells migrate
to discontinue the treatment regime, which can give rise to to lymph nodes and present the mycobacterial antigens
drug-resistant persister populations. Moreover, the treat- to the T cells in the lymph nodes. Upon antigen presen-
ment is expensive considering the income of the patients tation, naïve T cells differentiate into CD4+ and CD8+ T
in the developing countries and there is a significant cells and move back to the lungs.6 These T cells mainly T-
risk of the generation of multidrug-resistant (MDR) and helper 1 (Th1) cells and T-helper 17 (Th17) cells eliminate
extensive drug-resistant (XDR) strains of bacteria.4,5 In the bacteria by secretion of pro-inflammatory cytokines
some adverse cases, the side effects of the antibiotics cause such as IFN-γ, TNF-α, and cytolytic killing mechanisms,
liver diseases such as hepatitis with a mortality of 5% and respectively. The granuloma consisting of a core of infected
dampens the hosts’ T-cell immune response. Frontline macrophages, surrounded by epithelioid cells, lympho-
anti-TB drugs such as rifampin have adverse side effects cytes, neutrophils, and mesenchymal stem cells (MSCs)
like thrombocytopenia and itching, isoniazid causes is maintained by a delayed-type hypersensitivity (DTH)
neuropathy and T-cell reduction. Isoniazid, pyrazinamide, response to the bacterial antigens and tumor necrosis
and rifampin cause drug-induced hepatitis with high factor-alpha (TNF-α).6,7 In 90% of the infected individuals,
mortality rate.5 The side effects of the DOTS therapy have the M. tuberculosis remains in the granulomatous struc-
been schematically represented in Figure 1. Therefore, we ture for a very long time in a nonreplicating, asymptomatic
need an alternative therapeutic approach that may limit state called as the “dormant state.”7 Antigen-specific reg-
the side-effects associated with anti-TB therapy. ulatory T (Treg) cells and T helper 2 (Th 2) cells also get
A thorough understanding of the host immune response differentiated and counter the pro-inflammatory response
after M. tuberculosis infection is essential for the devel- in order to maintain homeostasis in the infected host.8
496 FATIMA et al.
FIGURE 2 The role of T cells in Tuberculosis pathogenesis and bacterial clearance
FIGURE 3 Evolution and the pillars of global TB eradication strategies
M. tuberculosis resides in the granuloma in dormant state ance out the toxicity associated with the drugs used in the
for decades by utilizing the host lipids and slowing down DOTS therapy and thereby rejuvenates the immune sys-
their replicative genes9 and wait for an opportunity such tem, to avoid or prevent disease reactivation is urgently
as a weakened immune system to reactivate and cause needed and would be very beneficial. These compounds
active disease.8 Elimination of actively dividing bacteria are mainly extracted from the plants that have been used
in the macrophages involves the role of macrophages and in traditional medicines for ages and have shown promis-
T helper (Th) cell responses whereas latent M. tubercu- ing effects. These compounds may be used either as drug
losis that is supported by the host MSCs requires myriad candidates or immunomodulatory agents with therapeutic
other factors and responses to get cleared up.9 Thus, Th1 potential against TB. Here, in this review paper, we would
and Th17 cells are the most important arms of adaptive mainly focus on ethnomedical agents/compounds, which
immunity that are responsible for maximum protection have been used as immunomodulators or as an adjunct
against tuberculosis infection.10,11 The crucial role of T cells therapy to reduce the toxicity of the DOTS therapy and
and their secreted cytokines in TB pathogenesis has been induce Th1 response and/or Th17 host protective immune
described in Figure 2. response simultaneously. This review is an effort to sum-
The major challenges faced by TB eradication pro- marize such compounds, known as phytochemicals with
grammes are the failure of BCG vaccination in protection their detailed mechanism of action.
against adult pulmonary TB, the length and side effects
of DOTS therapy, slow progress in new drug development 2 TREATMENT OF TUBERCULOSIS
approaches, and the emergence of drug resistance in TB USING TRADITIONAL MEDICINES
strains.1,5 Therefore, we urgently need an improved alter- DERIVED FROM PLANTS
nate therapeutic approach that can overcome these limita-
tions to deal with the deadly pathogen better. This is the Tuberculosis is an ancient disease as evident from the
utmost requirement of the 2035 end TB goal as set by the skeletal deformities found in the Egyptian mummies
WHO. We have described the pillars of global TB manage- belonging to 2400 BC, but it has been only around 2000
ment programme in Figure 3. Thus, in such a scenario a years since the first report of TB was documented in India
therapy that could be derived from natural plants to bal- and China.12 The traditional treatment of TB is practiced
FATIMA et al. 497
based on indigenous knowledge possessed by the local to help them thrive predators and pathogens. They are
healers. Earliest known treatment of this disease consisted the product of primary or secondary metabolism of the
of natural methods to manage TB and comprised various plant.26 These compounds have a history of being used
rituals derived from old traditional practices.13 Age-old in biomedical therapies and their therapeutic properties
practices related to TB treatment that have been handed are mainly associated with the presence of many differ-
down from generation to generation and are still part of TB ent compounds such as carotenoids, flavonoids, isothio-
therapy in various countries of South Africa and Asia.14–21 cyanates, indoles, monoterpenes, and phenolic acids.27
These traditional therapies although are not capable of The British Nutrition Foundation has classified these
completely eradicating the disease but are quite effective phytochemicals into four major categories: terpenoids,
in treating the respiratory disorders associated with TB and phenolics, nitrogen-containing compounds, and sulfur-
reducing the toxicity associated with antituberculosis ther- containing compounds.27 Till now, an ample number of
apy (ATT) as observed by the treatment provided in the phytochemicals have been screened but due to the lack of
patients by the traditional healers. Researchers all over the detailed analysis, this area of research has been continu-
globe are trying to find new antimicrobials from rich and ously neglected and therefore needs to be strengthened by
medically significant plant secondary metabolites belong- new research. Limited studies have been conducted so far
ing to the Indian subcontinent, South Africa, and other in exploring the potential role of phytochemicals in antitu-
eastern countries.15,16,18 berculosis therapy. Many researchers now giving attention
Since traditional treatment is practiced mostly on a local to the role of phytochemicals in TB therapy, as this therapy
scale therefore, the plants used for the treatment vary con- might help improve the effects of DOTS treatment. Some
siderably based on the country or place where it is fol- studies report the promising effect of the phytochemicals
lowed. Researchers from high TB burden countries have against M. tuberculosis bacteria.28,29 However, these stud-
reported different plant species used locally by traditional ies fail to compile the host protective mechanisms or the
healers for the treatment of TB and as the literature sug- immunotherapeutic use of these compounds. The domain
gests, most widely used plant species in the treatment of TB of phytochemical studies against M. tuberculosis is very
belong to Asteraceae, Asparagaceae, Amaryllidaceae, Api- broad and promising and is therefore in drastic need of fur-
aceae, Rutaceae, Solanaceae, and Leguminosae families ther exploration. We know that DOTS therapy while elim-
where plant parts such as roots, leaves, barks bulbs, and inating the bacteria dampens the host immune system. An
fruits contribute to the treatment of the patients.20,22,23,24 adjunct drug or compound that could prevent the damp-
These plant extracts do not eradicate the bacteria all on ening of the immune cells will prove to be a boon for TB
their own but they seem to play a very crucial role in man- treatment.
aging symptoms related to TB such as prolonged cough, In the following section, we have tried to summarize
chest pains, fatigue, appetite loss, and fever that increase the known phytochemicals, which have been used in TB
the level of discomfort in patients. These plant extracts or therapy. We have also discussed the antimicrobial activity
secondary metabolites exert expectorant, bronchodilator, of these phytochemicals with special impetus on their use
anti-inflammatory, and antipyretic effects. Since hundred in the prevention and treatment of tuberculosis.
years, plants such as Tussilago farfara and Pulmonaria
officinals are being explored for these properties in the
treatment of TB.25 Treatment of TB through the use 3.1 Allicin
of plants/phytochemicals constitutes a comprehensive
approach, which could give TB treatment an improved Garlic (Allium sativum) is a commonly used food ingre-
outlook. dient that has been widely acclaimed for its contribution
to human health for centuries. Garlic is used in the
prevention and treatment of a variety of infectious and
3 PHYTOCHEMICALS USED IN noninfectious diseases.30–32 Garlic is a strong antibacterial
TUBERCULOSIS THERAPY WITH THEIR agent and can inhibit the growth of both Gram-positive
POTENTIAL ROLE IN ATT and Gram-negative bacteria.33 Allicin is the main con-
stituent of garlic with potential antimicrobial properties
The word “Phytochemicals” refers to a variety of natu- (Figure 4A). It is an oxygenated sulfur compound, which
rally occurring and biologically active substances in plants is chemically known as thio-2-propene-1-sulfinic acid
that have protective or disease curing properties. The S-allyl ester. Allicin is an inhibitor of sulfhydryl metabolic
word “phytochemical” has been derived from the Greek enzymes. It interacts with the SH- group of the enzymes to
word “phyton,” which means plants.26 The phytochemi- exert its antimicrobial effects.34 Garlic has inexhaustible
cals are basically the chemicals produced in plants mostly research history against mycobacterial infection. In
as part of protection mechanism utilized by the plants 1944, Rao et al reported the reduction in M. tuberculosis
498 FATIMA et al.
F I G U R E 4 Structure of phytochemicals used for the treatment of tuberculosis. (A) Allicin, (B) Bergenin, (C) Curcumin, (D)
Epigallocatechin gallate, (E) Piperine, (F) Tetrandrine, (G) Ursolic acid and Oleanolic acid, (H) Andrographolide, (I) Resveratrol, (J)
Thymoquinone, (K) Reserpine, (L) Pasakbumin A, (M) Gingerol, (N) Silymarin, and (O) Glycyrrhizin (Adapted from PubChem)
replication upon treatment with allicin. They observed a surface receptors responsible for M. tuberculosis entry.41
bacteriostatic effect at low concentrations and a bacterici- Experiments done in mice model establish that treatment
dal effect at higher concentrations of the compound.35 A of infected mice with allicin/garlic extract leads to a sig-
further study by Ratnakar et al in 1995 reported that garlic nificant reduction in bacterial burden mainly due to host
was able to inhibit the growth of isoniazid-susceptible and protective Th1 response, which eliminates the pathogens
-resistant strains, H37Rv and TRC-C1193, respectively.36 In in a much lesser time duration compared to the conven-
the following years, it was reported that allicin reduces M. tional treatment coarse. Furthermore, garlic extract also
tuberculosis burden in the host by increasing the activity of has been shown to reverse the immune-dampening effects
the enzyme, glutathione peroxidase.37 Another interesting associated with the use of standard TB drugs.41 In a nut-
in vitro study compared the antitubercular activity of shell, allicin/garlic extract showed very promising results
Allium sativum with standard antibiotics using the disc in infected mice when used alone or as an adjunct to
diffusion method.38 These results established that garlic classical antibiotics for both drug-sensitive and -resistant
exhibited maximal activity against multiple drug-resistant strains. Another compound derived from garlic, known
M. tuberculosis as well.38 In 2006, Hasan et al studied the as ajoene, has shown tremendous effectiveness in TB
reduction in Reactive Oxygen Species (ROS) expression treatment due to its ability to induce autophagy and ROS
induced by the bacilli, upon treatment with allicin.39 In synthesis.40–42 The therapeutic value of these compounds
2014, Vishwanathan et al reported in an in vitro study that and their broad-spectrum antimicrobial activity suggests
garlic extract and garlic oil both show decent antimycobac- garlic and its derivatives can be a beneficial addition to
terial activity when compared to standard drugs, using ATT.
zone inhibition method.40 A recent study by Dwivedi et al
has given some strong proofs to establish the therapeutic
potential of allicin in the pathogenesis of tuberculosis. 3.2 Bergenin
Allicin/garlic extract displays direct killing of Mycobac-
teria and leads to the induction of pro-inflammatory Bergenin is a natural secondary metabolite found in differ-
cytokines in macrophages while also limiting M. tubercu- ent parts of several plants.43 It is also known as cuscutin
losis infection inside the cells by interacting with the cell and is a trihydroxybenzoic acid glycoside (Figure 4B). It is
FATIMA et al. 499
one of the active phytochemicals in herbal and ayurvedic Curcumin is beneficial in the treatment of diseases
formulations. Bergenin has a myriad of ethanomedical such as cancer, diabetes, kidney disorder, and neurocog-
properties like antibacterial, antiviral, antifungal, anti- nitive disorders by modulating the expression of Nrf2
tussive, anti-inflammatory, antitumor, antidiabetic, and gene. The anti-inflammatory role of curcumin is exhib-
wound-healing properties.44 Of late, the effectiveness and ited mainly via the downregulation of NF-κB gene signal-
properties of bergenin have been studied by different ing and its downstream genes and proteins.58,59 In can-
groups in different disease contexts. Nunomora et al did cer, curcumin downregulates the expression and activ-
some initial research on the existing anti-inflammatory ity of cyclooxygenase (COX-2) gene along with reduced
properties of bergenin.45 Later, in 2016, Khan et al activity of inducible nitric oxide synthase (iNOS) by sup-
reported that bergenin has remarkable activity against pressing the transcription factor NF-κB. This in turn has
the chloroquine-sensitive Plasmodium falciparum and also a role in suppression of progressing tumorigenesis.60,61 It
shows antioxidant properties.46 Recently Dwivedi et al acts effectively to eliminate M. tuberculosis in TB-infected
have demonstrated the effectiveness of this phytochemical patients. Therefore, it would be very interesting to further
in tuberculosis management. Their investigation revealed explore the action mechanism of this phytochemical in
that bergenin treatment in infected macrophages led to the tuberculosis treatment. Curcumin is also reported to pre-
activation of the MAP kinase and ERK pathways, which vent anti-TB drug-induced hepatic damage.62 It exhibits
further lead to TNF-α, nitric oxide (NO), and Interleukin- dose-dependent inhibition of intracellular growth for M.
12 (IL-12) production. Further, when observed in murine tuberculosis, H37Rv.63 It is a potent inducer of apopto-
model, bergenin induces the expression of Th1 and sis, which is an effector mechanism used by macrophages
Th17 immune responses and limit the replication of the to kill intracellular pathogens. The antimicrobial poten-
bacteria.47 They also studied that a combination therapy tial of macrophages is increased upon treatment with cur-
of DOTS along with bergenin reverses the immune dam- cumin, by an upregulation in the expression of apoptosis
age and reduces the duration of clearance of M. tubercu- and autophagy genes.64
losis in mice.48 Therefore, to summarize cotreatment with Although curcumin has myriad health benefits, it is rel-
bergenin and isoniazid reduces the side effects associated atively unstable and has poor bioavailability because of
with isoniazid such as immune dampening, while promot- being rapidly eliminated from the body.65 To overcome
ing the generation of long-lasting, central memory T-cell this limitation, Baldwin et al synthesized monocarbonyl
responses.47,48 Notably, bergenin acted well in the elimina- analogs of curcumin and tested for their efficiency in
tion of drug-resistant strains as well. Therefore, bergenin reducing the replication of M. tuberculosis and Mycobac-
can be a prospective adjunct to current TB therapy. terium marinum (Mm) and found a remarkable reduc-
tion in the number of Mm and M. tuberculosis using sev-
3.3 Curcumin eral analogs.66 This study paved the way for synthesis of
more structural analogs that could interact better with the
Curcumin, also known as “Indian Yellow Gold” is a frontline anti-TB drugs. Another modification of curcumin
polyphenol, diferuloylmethane, which is responsible for that is nanoparticle-formulated curcumin was generated
the bright yellow-orange color of the Indian spice turmeric by Tousif et al and studied for its effect against active TB
(Curcuma longa) (Figure 4C). Turmeric is the most com- in mice model. Nanocurcumin exhibits a fivefold increase
monly consumed spice in India. It has been used in in bioavailability compared to curcumin extracted from
India and China since time immemorial, in traditional turmeric and is around ∼200 nm in size.67
treatments and as an antibiotic.49 The compound “cur- As is the demand of TB treatment, curcumin nanopar-
cumin” was isolated by German scientists Vogel and Pel- ticles effectively reverse the hepatotoxicity conferred
letier in 1815.50 Curcumin has numerous healing prop- by antitubercular drugs and reduce the incidence of
erties that have been a topic of research by scientists reinfection and reactivation in mice. Thus, it compensates
all over the world.51,52 The most studied activity of cur- for the major shortcoming of the DOTS therapy by short-
cumin in the past years are its antitumor effects and ening the time required to achieve complete clearance
antibacterial properties.53 In 1949, Schraufstätter and Bernt of the bacilli from the lung and thereby diminishing
described the bactericidal activity of curcumin against the probability of generation of drug resistance among
various bacteria including the TB causing pathogen, M. M. tuberculosis strains.67 Therefore, an adjunct therapy
tuberculosis.54 The antibacterial potential of curcumin has comprising nanocurcumin together with DOTS therapy
gained tremendous attention in the past few decades owing could be included in the treatment of tuberculosis.67
to its extraordinary antibiotic properties.55,56 Curcumin Lately, they further tested curcumin nanoparticles for
has anti-inflammatory and antioxidative potential and tar- their possible role in augmenting the effectiveness of
gets several pathways important for bacterial survival.57 Mycobacterium bovis (BCG) vaccine. They found that
500 FATIMA et al.
curcumin nanoparticles improve the host protective gene, which has been studied for its involvement in inhi-
ability of BCG by generation of strong and lasting memory bition of phagosome maturation during M. tuberculosis
response by inducing T-central memory (TCM) cells of the infection.83 This study describes that epigallocatechin-3-
Th1 and Th17 lineages.68 Most recently Jahagirdar PS et gallate downregulates the transcription of TACO gene
al coencapsulated rifampicin and curcumin in polymeric in human macrophages by inhibiting the Sp1 transcrip-
nanoparticles and used it in infected macrophages. These tion factor, which led to inhibition of mycobacterium sur-
nanoparticles improved M. tuberculosis clearance from the vival within macrophages.83 These studies emphasize that
macrophages validating that these rifampicin-curcumin green tea polyphenol specifically EGCG may be used as
nanoparticles may be a promising therapy in future.69 an adjunct in the prevention of tuberculosis infection and
These studies open new dimensions to implement the help in reversal or reduction in the side-effects of the strong
host-protective role of curcumin in tuberculosis treatment. antibiotics used in the TB treatment regime. Its role as an
immunotherapeutic should also be explored so that this
polyphenol can be incorporated in the treatment proce-
3.4 Epigallocatechin-3-gallate dure.
Tea is an extensively consumed drink worldwide. Among

the different varieties of tea consumed, black tea and green 3.5 Piperine
tea possess maximum antioxidant properties.70 Many stud-
ies have validated the role of polyphenols in tea, in The pharmacological activities of black pepper (known as
improving the levels of oxidative stress, in different dis- the king of spices) are because of the presence of various
ease conditions.71,72 Epigallocatechin gallate (EGCG) is phytoconstituents in it, which confer antipathogenic prop-
one of the principal polyphenolic compound found in erties to it. Of all the available phytoconstituents, an alka-
the leaves of the green tea plant known as Camellia loid, piperine is the most important (Figure 4E). Piper-
sinensis (Figure 4D). Green tea leaves have been reported ine is a natural compound present in Piper nigrum and
to possess anticancer, anti-inflammatory, and antioxidant Piper longum and is reported to have anti-inflammatory,
properties.73 According to a study by Ahmed et al, EGCG antimicrobial, antifungal, antioxidant, and anticarcino-
suppresses the IL-1 beta-induced activity and expression genic effects.84 It forms an essential component of tradi-
of COX2 and nitric oxide synthase-2 (NOS-2) in human tional medicines for ages. Piperine has always been a cen-
chondrocytes.74 Another study related to chronic kidney ter of attraction in research due to its potential of being
disease suggests that EGCG attenuates oxidative stress and an enhancer of bioavailability of drugs through the inhi-
inflammation via regulation of NF-κB and Nrf2/HO-1 sig- bition of CYP3A4 and human P-glycoprotein, particularly
naling pathways.75 cytochrome P450-mediated pathways.85,86 In tuberculosis
EGCG has shown to be quite impressive in the treat- treatment, piperine acts as an inhibitor of bacterial efflux
ment of tuberculosis. Epidemiological evidence supports pumps and an immunomodulatory compound.87 Piperine
the role of tea drinking in the reduced incidences of TB. is efficient against the multidrug-resistant strains along
Research done on the effect of green tea polyphenols on TB with eliminating drug-sensitive strains.88 Chabamide is
suggests that regular consumption of green tea reduces the a dimer of piperine and is isolated from the stems of
risk of active TB in infected individuals.76,77 However, the P. chaba. This dimer exhibits antituberculosis activity
reason for the association between tea drinking and tuber- against M. tuberculosis.89 Piperine induces the activity
culosis is still not clear. Catechin called epigallocatechin- of the proinflammatory Th1 response, thereby, increas-
3-gallate has been mostly studied in terms of its effects on ing lymphocyte proliferation and increased NO secre-
TB treatment. In murine model studies and in TB patients, tion by the macrophages. The cotherapy of piperine and
green tea extract has been utilized as adjuvant therapy in rifampicin (RIF) shows a 1.4-0.8 log decrease in the bac-
tuberculosis treatment owing to its ability to reduce oxida- terial number in the lungs of mice, which is signifi-
tive stress.78,79 Green tea extract also decreases the risk cantly higher than RIF alone.89 Therefore, piperine can
of delay in sputum smear conversion in pulmonary TB be administered in a combination treatment along with
patients possibly by having an impact on the integrity of anti-TB drugs owing to its upregulation of Th1 immune
the mycobacterial cell wall.80,81 Recently Grüber et al dis- response, to improve the overall drug response in immune-
covered that EGCG could possibly bind to mycobacterial compromised patients.90 Piperine has also been studied to
ATP synthase and cause the inhibitory effects such as dys- exhibit a strong EtBr efflux inhibitory effect in M. smeg-
regulated energy production and cell wall biosynthesis.82 matis, which possibly makes it an inhibitor of the intrin-
Another study by Anand et al has revealed the effect sic EP system in mycobacteria.91 A study by Sharma et al
of polyphenols derived from green tea on the TACO shows that piperine reduces the the minimum inhibitory
FATIMA et al. 501
concentration (MIC) and improves the antimicrobial potential is mostly unknown; more studies are needed in
action of rifampicin in all bacilli tested.92 In the presence of order to explore its maximum potential in TB cure.
rifampicin, M. tuberculosis RIF-R showed overexpression
of efflux pump Rv1258c. Piperine along with rifampicin
3.7 Ursolic acid (UA) and oleanolic acid
inhibits the expression of Rv1258c and thus may improve
(OA)
the bacterial killing efficiency of rifampicin.92 A recent
investigation has proposed that piperine slows down M.
Ursolic acid (UA) and oleanolic acid (OA) are ubiq-
tuberculosis growth through RNA polymerase inhibition,
uitous triterpenoids found in many kinds of medici-
which is additional knowledge from what was previously
nal plants such as Chamaedora tepejilote and Lantana
known.93 Lately, the role of piperine as a bioenhancer in
hispida (Figure 4G). More than 700 research articles
tuberculosis treatment is being studied upon. Risorine,
have discussed its role in disease management, mak-
a novel combination of rifampicin (200 mg), isoniazid
ing it a triterpenoid of huge importance.102 These triter-
(300 mg) along with bioenhancer piperine (10 mg), has
penic acids have been commonly used in the treatment
been reported to be highly useful and safe in the treat-
of respiratory ailments such as cough, bronchitis, colds,
ment of TB.94 Risorine furnishes more rifampicin in blood
and pneumonia.102 UA and OA have several biological
compared to the gastrointestinal (GI) tract as well as main-
and pharmacological effects, including antibacterial,103,104
tains higher blood levels compared to the conventional
antiviral,105 antiparasitic,104 antioxidant,106 and antitu-
rifampicin, and with a better safety profile.95 To put it all
moral activities.107 Recent researches have revealed the
together, piperine has immense therapeutic applications
immunomodulatory and mycobactericidal effect of these
and can be recognized as an important nutraceutical in
triterpenoids on TB pathogenesis.108,109 UA reportedly
tuberculosis treatment owing to the essential adjunct role
activated NF-κB signaling pathway and subsequently
it has shown to play during the treatment course.
enhanced the level of NO, ROS, and TNF-α while reduc-
ing the level of TGF-β1.110–112 The combination of UA
and TB drugs has shown to display synergistic interac-
3.6 Tetrandrine tion in the treatment of TB.113 A study by Sonia López-
García et al states that OA and UA have immunomodula-
Tetrandrine is a natural compound that is extracted from
tory effects on M. tuberculosis-infected macrophages.113 OA
Stephania tetrandra root. This phytochemical, is a mem-
and UA reduce M. tuberculosis growth in macrophages by
ber of isoquinolines and a bisbenzylisoquinoline alkaloid
enhanced production of NO, TNF-α, and ROS. This is also
(Figure 4F). Stephania tetrandra plant has been exten-
accompanied by overexpression of certain cell membrane
sively used in the Chinese medicinal system since ages.96
receptors like CD36 and TGR5.114 These are scavenger
Several studies have studied the efficiency of tetrandrine
receptor and G-protein coupled receptors responsible for
as an inhibitor of calcium channels and an inducer of
lipid accumulation and mediating bile acid synthesis. It
apoptosis.96,97 This compound has been reported to be
has been reported that these triterpenes exert their antimy-
effective in various bacterial and inflammatory health
cobacterial effects by the conversion of macrophages from
issues.98–100 This phytochemical also lowers the plasma
M2 to M1 phenotype.114 Both compounds, alone and in
glucose level by increasing glucose utilization in hepato-
combination, have been studied to be effective against
cyte for glycogen synthesis. Although quite effective in the
intracellular bacteria even at low doses; with a higher
treatment of many diseases, its effectiveness in the treat-
expression of IFN-γ and TNF-α in the lungs compared to
ment of tuberculosis is not very well documented. Few
untreated control. Therefore, UA and OA have antimicro-
studies have also been conducted on the role of tetrandrine
bial activity together with an immune-stimulatory poten-
in the reversal of drug resistance in a group of both iso-
tial that can be used for the control of mycobacterial
niazid and ethambutol-resistant clinical strains.98 Tetran-
infection.113
drine treatment together with isoniazid or ethambutol was
effective in reducing the minimum inhibitory concentra-
tion of the dual-resistant strain from drug resistance to 3.8 Andrographolide
the sensitive level for both drugs. This study suggested
that the combination therapy of tetrandrine with frontline Andrographolide is a bicyclic diterpenoid compound
anti-TB drugs, isoniazid or ethambutol increased the effi- (Figure 4H) found in Andrographis paniculata, which has
cacy of the drug and may help in decrease in the drug been widely used in traditional medicines across Asian
dosage, thereby minimizing the ill-effects associated with countries as an immune booster. It has antibacterial,115
the drug.101 However, since there is a lot of ambiguity in the antimalarial,116 analgesic,117 antihepatotoxic,118 and
mechanism of action of tetrandrine and its immunogenic immunomodulatory properties.119 Studies in the murine
502 FATIMA et al.
model have shown that andrographolide has been effec- that mice treated with resveratrol are more resistant to
tive in significantly reducing Experimental Autoimmune M. tuberculosis infection compared to untreated control as
Encephalomyelitis (EAE) symptoms. A recent study by they harbored less bacterial loads, and lower lung impair-
Liao et al has shown the potential of this diterpenoid in the ment as seen through histological studies.132 In 2019, Rosa
treatment of steroid-resistant airway hyperresponsiveness et al developed isoniazid-resveratrol cocrystals (INH-RES)
in patients with asthma.120 The immune-stimulatory to increase the solubility, stability, and bioavailability of
properties of Andrographis paniculata pave way for its resveratrol for the treatment of cutaneous TB, locally and
role in the treatment of gastrointestinal and respiratory found it to be effective in disease cure.133 But, to date, we do
tract infections.121,122 These studies make this compound not have much research done on the immunomodulatory
very promising to be used against M. tuberculosis. How- and bactericidal effects of this compound. It would also be
ever, very less research has been carried out globally to of great interest to further study the contribution of this
examine its in vitro and in vivo potency in the case of compound in TB disease.
M. tuberculosis. Though andrographolide has shown to
be cytotoxic against M. microti, M. bovis, and M. canettii,
studies for its role in the treatment of M. tuberculosis 3.10 Thymoquinone
are limited.123,124 In a study by Prabhu et al, docking
analysis and molecular simulation establish aminoglyco- Nigella sativa (black cumin) is a medicinal plant having
side 2-N-acetyltransferase (AAC) as a possible target of the main active compound thymoquinone (2-isopropyl-
andrographolide in M. tuberculosis.125 AAC is an enzyme 5-methyl-1, 4-benzoquinone) (Figure 4J). This compound
that plays a key role in acetylation of an important inter- has potent antibacterial, anti-inflammatory antioxi-
mediate of mycothiol synthesis, which is a major reducing dant, antimutagenic, antitumor, and hepatoprotective
agent in mycobacteria in-charge of regulating the cellular effects.134,135 Thymoquinone is the main constituent of
redox potential.126 Apart from this, AAC may catalyze the volatile oil extracted from Nigella sativa plant. It has
the acetylation of the 2′ hydroxyl or amino group of a proved to restrain the development of pathogenic bacteria
broad spectrum of aminoglycosides and thereby confer by inhibiting the formation of biofilms, which shelter the
resistance to aminoglycosides.127 This in silico study gives microorganism from harmful factors of the environment
us a direction to explore the vital role of andrographolide such as the host immune system and antibiotics.136
as an antimycobacterial agent that targets aminoglyco- Besides, when used in a synergistic therapy with standard
side 2-N-acetyltransferase in M. tuberculosis. As it has drugs, it reduces the minimum inhibitory concentration
immunomodulatory characteristics, further in vivo studies of the drugs.137 Additionally, it has been used as an anti-
and clinical trials are needed to substantiate its crucial role fungal agent against some significant parasitic pathogens
as a promising drug or adjunct in tuberculosis treatment. including Candida albicans.138,139 It has not much been
used as an antimicrobial and a lot of research is needed to
exploit its potential in the treatment of infectious agents.
3.9 Resveratrol Thymoquinone is reported to have in vitro antitubercular
activity and has proved to be significantly effective against
Resveratrol is a natural polyphenolic phytochemical (Stil- drug-resistant M. tuberculosis strains by inhibiting the hep-
benoid) that is extremely enriched in red wine, the skin atotoxic effects of anti-TB drugs.140,141 The study delineated
of grapes, peanuts, and some berries (Figure 4I). It is syn- antimycobacterial effects of thymoquinone, which suc-
thesized by the plant in response to a pathogenic attack cessfully hinders the replication of M. tuberculosis H37Rv
or under stress conditions. This stilbenoid is found to be and the extremely drug-resistant, XDR strain inside Raw
the focal point of a plethora of investigations because of its 264.7 macrophage cell line. It also has been described to
extensive use in treatment of different diseases. It has been inhibit secretion of pro-inflammatory cytokines and NO
used worldwide in the treatment of viral diseases, cancer, in different cell lines after bacterial infection.142 However,
and neurological diseases owing to its anti-inflammatory, we still have very preliminary research on the use of
antioxidant, and chemotherapeutic properties.128–131 It has thymoquinone as an adjunct therapy in TB, which needs
antimycobacterial activity against nonvirulent strains of to be elaborately studied in future.
TB such as H37Ra and BCG. Hong Yang et al have reported
in an in vitro study that pretreatment with resveratrol in M.
tuberculosis-infected macrophages, inhibits the activation 3.11 Reserpine
of pathways such as TAK1, MAPK, and NF-κB and there-
fore resulting in the reduction in the levels of proinflam- Reserpine is an alkaloid that is extracted from the roots of
matory cytokines.132 Furthermore, it has been observed Rouwolfia serpentine plant (Figure 4K). It is efficacious in
FATIMA et al. 503
the treatment of high blood pressure and other heart dis- pharmacological activities, Eurycoma longifolia is widely
eases by reducing arterial pressure. The antihypertensive known for its anticancer potential.157 However, the con-
effects of reserpine are due to the antinoradrenergic effects tribution of specific compounds extracted from E. longi-
it possesses.143 It blocks the vesicular monoamine trans- folia that control intracellular M. tuberculosis growth has
porters such as catecholamines and irreversibly inhibits not been explored adequately. Few recent studies throw
the internalization and stowage of dopamine in the synap- light on the role of Pasakbumin A in tuberculosis as it
tic vesicles making it very helpful in treating hyperten- has anti-TB activity against the virulent M. tuberculosis
sion and psychiatric disorders.144,145 Reserpine also has strain. Research done till date, state that pasakbumin A
shown the ability to inhibit the formation of biofilms by works through the activation of ERK1/2-intermediated
inhibiting the metabolic processes of the bacteria form- signaling pathways and autophagy.158 A combination of
ing the biofilm.146 Its role as an efflux pump inhibitor pasakbumin A together with rifampicin has been used to
makes the bacteria susceptible to drug treatment.147 Addi- clear the bacteria remarkably by high TNF-α production
tionally, it has been reported that reserpine when adminis- and autophagy in M. tuberculosis-infected macrophages.158
tered together with a standard antibiotic led to the reduc- This study anticipates the imperative domain of pasakbu-
tion in the MIC of the antibiotic, such as tetracycline by min, as a much potent drug that has the capacity of being
fourfold in treatment of B. subtilis infection.148 Reserpine used as a new drug or as an alternate treatment in TB ther-
has shown significant effects on the pathogen’s resistance apy. More substantial research is required to establish it as
to various anti-TB drugs during mycobacterial infections. an anti-TB drug.
This efflux pump inhibitor increases the susceptibility of
both BCG and M. tuberculosis strains to the drug isoni-
azid and also to pyrazinamide by blocking the pyrazinoic 3.13 Gingerol
acid efflux pump.149,150 Jaiswal et al, in 2017, have observed
that in the presence of reserpine, there was a reduction Ginger is a common plant that grows in Asia and Africa
in the MIC of isoniazid and it was effective against both and is found abundantly in China and India (Figure 4M).
drug-susceptible and drug-resistant isolates.151 Another It is traditionally used to treat various ailments such as
study used the derivatives of reserpine in the treatment headaches, colds, cough, flu, asthma, arthritis, muscular
of M. tuberculosis owing to its extraordinary antioxidant discomfort, and any sort of inflammation.159,160 Now, sci-
properties.152 It has also been employed for the elimina- entific studies have also proven the medicinal usage of gin-
tion of nonreplicating M. tuberculosis through the use of its ger to cure symptoms associated with TB.161,162 The use
efflux pump inhibitor action.153 However, there is no work of ginger in a variety of diseases is solely because of the
done on its role as a potential immune booster. It has been compounds present in it, such as gingerols, shogaols, gin-
reported that reserpine acts by blocking catecholamines. gerdiones, gingerdiols, and paradols.163 As known by the
Grailer et al152 and Nguyen et al154,155 have reported in dif- available literature, garlic extracts exhibit weak antibacte-
ferent studies that catecholamines acts on the immune rial properties but it is the essential oils obtained from gin-
system. It acts on the host by promoting activation of ger rhizomes that are known to be significantly antibacte-
M2-like macrophage activation. Catecholamines act on rial. A random study conducted in pulmonary TB patients
both MyD88-dependent and MyD88-independent signal- revealed that a combination therapy of ginger together
ing pathways through the activation of TLRs.154,155 There with DOTS gave significantly encouraging results.164 A
is no knowledge of how this drug acts on the host immune recent paper has reported that [6]-Gingerol has immense
system. Therefore, reserpine can be categorized among the potential to be used as an adjunct drug, along with
phytochemicals, which need immediate attention from the isoniazid, an antibiotic of the DOTS regime. Gingerol
researchers as it is a natural compound with minimum or showed excellent activity against drug-resistant and dor-
no side effects. If it can be explored as immune booster, it mant bacilli.165 Some investigators also confirm that the
would probably solve the cons associated with the DOTS bioactive phytochemicals present in ginger lower the level
therapy. of effective lipid mediators such as prostaglandin and
leukotriene in the treated individuals via lowering the
levels of 5-lipoxygenase or prostaglandin synthase, which
3.12 Pasakbumin A further leads to a decrease in the production of pro-
inflammatory cytokines highlighting its likely effective-
Pasakbumin A is a natural compound extracted from the ness in limiting the inflammation associated with tuber-
medicinal plant, Eurycoma longifolia, which is a com- culosis treatment.166–168 The use of gingerol may help the
monly used in the treatment of fever, malaria, ulcers, patients avoid steroid treatments and thus their associated
and TB (Figure 4L).156 Apart from these above-mentioned side effects. Therefore, it would be very intriguing to look
504 FATIMA et al.
at the immune-modulatory consequences of including gin- crucial to be studied more extensively so that its immune-
gerol as an adjunct therapy in the TB treatment, which may modulatory role can be further confirmed. This phyto-
add to the efficacy of the therapy. chemical demonstrates great promises and may be studied
in reinfection and reactivation studies.
3.14 Silymarin
3.15 Glycyrrhizin
Silymarin is the biologically active compound derived from
the seeds of milk thistle plant (Figure 4N). Milk thistle Glycyrrhizin is a triterpene glycoside, the major active
has been used since ages in treating liver ailments.169 The compound present in the roots of the perennial plant Gly-
flavonoid silymarin consists of three phytochemicals, sily- cyrrhiza glabra, also commonly known as licorice (Fig-
bin, silidianin, and silicristin. Of the three phytochemi- ure 4O).181 Its active components are glycyrrhetinic acid,
cals, silybin is the most important for the effectiveness flavonoids, hydroxyl coumarins, and b-sitosterol. G. glabra
of this compound in treatment of diseases.170 Silymarin has been used in traditional medicines for the treatment of
is used in patients with a history of alcohol use and also various diseases and is recognized since ancient times for
in drug-induced liver injuries. It is also recommended in its ethnopharmacological properties. Glycyrrhizin is most
incidences of mushroom poisoning and in chronic hep- widely used in the treatment of liver problems, as an anti-
atitis B.171–173 Silymarin has proved to possess significant inflammatory, laxative, antidepressive, and antidiabetic
hepatoprotective activity, as revealed by various animal and for the treatment of stomach ulcers.182–183 This is due
model studies. It has come out to be quite safe without to the anti-inflammatory and immune-boosting proper-
any major side-effects, which makes it a phytochemical ties of glycyrrhizin. Several investigators have documented
with quite promising adjuvant potential to be used in anti- the role of glycyrrhizin in the treatment of liver diseases
TB treatment.174,175 Researchers have established that sily- such as reducing inflammation, liver fibrosis, and promot-
marin has the potential to be used as a prospective drug ing tissue regeneration. It has been reported to possess
to inhibit liver damage, reestablish the membrane poten- anti-inflammatory and antiapoptotic effects by the sup-
tial and restore the function and expression levels of hep- pression of TNF-α and caspase-3.184 Glycyrrhizin also leads
atic enzymes.176,177 The hepatoprotective effects of sily- to the upregulation of proliferating cell nuclear antigen
marin have been confirmed in many studies. Neverthe- (PCNA), suggesting its role in tissue regeneration, in case
less, its experimental efficacy in minimising the level of of liver injury.185 These properties make glycyrrhizin use-
liver damage induced by ATT is a topic of conflict among ful as an anti-inflammatory agent, as an antitumor treat-
the researchers. Luangchosiri and group performed clin- ment, and for the treatment of viral infections such as
ical trial studies to demonstrate the efficacy of silymarin hepatitis B and SARS and in parasitic infections. Due to
in treatment of active TB patients.176 They found that sily- its use in treatment of different diseases, the researchers
marin displayed a positive hepatoprotective effect after 4 have started to look into the antimicrobial potential of
weeks of drug administration. They reported that liver glycyrrhizin and have evaluated its potential against both
damage in the silymarin-treated group was significantly drug-sensitive and -resistant strains of microorganisms.186
lower than in the control group. However, contrary to the It has been found to possess significant antimicrobial prop-
previous report, Marjani et al169 and Zhang et al178 did not erties against both Gram-positive and Gram-negative bac-
observe any significant consequence of using silymarin in teria. It has also been used in the treatment of H. pylori
drug-induced hepatitis patients. However, we need more infection and in the treatment of peptic ulcers.186 Gly-
research and clinical trials before we establish the role cyrrhizin has also been studied to inhibit the propagation
of silymarin in TB drug-induced hepatotoxicity because of methicillin-resistant S. aureus (MRSA) by its bacterio-
of the variation in result due to limitation in sample size static and bactericidal activity.186 Recently, the role of gly-
and variation in the population studied. Silymarin has cyrrhizin in the treatment of intracellular pathogen, M.
been reported to possess significant anti-inflammatory and tuberculosis has been deciphered albeit to a limited extent.
immune-modulatory capacity as well. Silymarin has been It has shown to reduce the MIC of the drugs used in con-
described to contribute in TB treatment by increasing the ventional TB therapy when used in combination.186 How-
expression level of pro-inflammatory Th-1 cytokines. It has ever, still we do not know the mechanism employed by gly-
shown to eliminate both the MDR and drug-sensitive M. cyrrhizin for its anti-TB effectiveness. The initial results of
tuberculosis. However, the mechanism responsible for the it acting as bactericidal agent, are convincing enough to
fundamental activity of the extract of silymarin is still not further investigate the potential of this phytochemical as
known.179,180 The antioxidant properties associated with an adjunct in ATT. All of these discussed compounds are
this compound and the research done to date make it very summarized in Table 1.
FATIMA et al. 505
TA B L E 1 List of phytochemicals having antimycobacterial properties

Name of Phytochemical Plant of origin Mechanism of action against M.tb References
Allicin Allium sativum (Garlic) Antimycobacterial, stimulates Th1 response, antihepatotoxic 30-42
Bergenine Different parts of a number of Anti-inflammatory, induces Th1, Th17 immune response, 43-48
plants (Shorea robusta) reduces the length of treatment
Curcumin Curcuma longa (Turmeric) Antibacterial, immunomodulatory, enhances BCG efficacy 49-69
Epigallocatechin gallate Camellia sinensis (Green Tea) Reduces oxidative stress, impacts integrity of mycobacterial 70-83
cell wall, antioxidant
Piperine Piper nigrum (Black pepper) Antimycobacterial, NO production, stimulates Th1 response 84-95
Tetrandrine Stephania tetrandra Reversal of drug resistance 96-101
Ursolic acid and Oleanolic Chamaedora tepejilote, Lantana Antimicrobial, immunomodulatory, promotes th1 response 102-114
acid hispida
Andrographolide Andrographis paniculata Antihepatotoxic, antibacterial, immunomodulatory 115-127
Resveratrol Grapes, berries, peanuts antibacterial, increases resistance to M.tb infection 128-133
Thymoquinone Nigella sativa (Black cumin) Effective against drug-resistant strains, hepatoprotective 134-142
Reserpine Rouwolfia serpentine Efflux pump inhibitor, increases the susceptibility of 143-155
bacteria to antibiotics
Pasakbumin Eurycoma longifolia Autophagy inducer, antibacterial 156-158
Gingerol. Zingiber officinale (Ginger) Anti-inflammatory, antibacterial, antioxidant 159-168
Silymarin Silybum marianum (Milk thistle) Hepatoprotective, anti-inflammatory, immunomodulatory 169-180
Glycyrrhizin Glycyrrhiza glabra (Licorice) Anti-inflammatory, immune booster 181-186
4 THE ROLE OF PHYTOCHEMICALS tion of Th1 immune response selectively, with the simul-
IN TUBERCULOSIS MANAGEMENT: AN taneous downregulation of the Th2 immune response.191
IMMUNOLOGICAL AND HOST Any such compound, natural, or synthetic that can act
HEPATO-PROTECTIVE PERSPECTIVE as an inducer of selective immune response is referred to
as an immunomodulator.192 Immunomodulators alone are
Tuberculosis is a disease characterized by both microbial not capable of getting rid of the bacteria but act on the
infection and tissue inflammation. The innate immune host immune system to make it more potent in eliminating
cells particularly the macrophages and dendritic cells the pathogen. Recently, the use of plant-based compounds
encounter M. tuberculosis in the lung alveoli and initiate an as immunomodulators has gained huge importance. A
early antimycobacterial immune response in order to pre- lot of research is being done in evaluating the usefulness
vent the progression of the disease.187 However, M. tuber- of plants and compounds derived from them in boosting
culosis has evolved a number of strategies to keep the host the immune system against M. tuberculosis. These com-
immune system at wonder. Susceptible individuals may pounds are used with the sole purpose of balancing the pro-
have suppression in the level of T helper type 1 cells (Th1) inflammatory cytokines and anti-inflammatory cytokines,
responses, which is a result of reduction in the produc- which is disturbed by the bacilli for its favoured survival
tion of IL-12. Less Th1 response leads to reduced levels of in the host system.192 Of the known phytochemicals or
proinflammatory cytokines and high expression levels of plant secondary metabolites whose immunomodulatory
anti-inflammatory cytokines.188 The side-effects of DOTS properties are very well established are very few. Most of
therapy on the host, including the sharp decline in pro- the secondary metabolites have not been tested for their
tective CD4+ T-cells makes the host vulnerable to rein- immune-boosting potential and their role in preventing
fection and reactivation of the disease.189 However, the the reactivation of the disease. As their role in the pre-
use of anti-inflammatory drugs along with conventional vention of hepatotoxicity and improving the overall health
antibiotic treatment controls the inflammation associated of the patient is gaining huge attention, these compounds
with the disease and increases the overall effectiveness may in future qualify to be used in synergistic treatment
of ATT.190 But, because of continuous use of these anti- approach, along with the conventional DOTS regimen for
inflammatory drugs or steroids the host encounters severe improving the overall quality of the treatment and reduc-
side-effects; making such treatment nonadvisable for the ing the side effects involved with the ATT.
patients. Therefore, immunologists all over the world are Alcoholic extract of Coleus scutellarioides (Miana leaves)
looking for an approach, which could lead to upregula- induce the proinflammatory T-lymphocyte response by
506 FATIMA et al.
FIGURE 5 The mechanism of action of immunomodulators against TB
increasing the levels of IFN-γ and TNF-α, thus acting as 3 pathway.58 Moreover, the incorporation of curcumin
an immunomodulator.192 The killing of M. tuberculosis nanoparticles to the DOTS therapy has been studied to
by treatment of miana extract is not due to direct inhi- induce the activation and progression of TCM and thereby
bition of bacterial proliferation; instead, it is a result of prevented reinfection and reactivation of the disease in
host immunomodulation by the compound.192 Similarly, mice.195 Administration of antibiotics during ATT leads
immunomodulatory activities of other plant secondary to serious side-effects in the host, such as hepatotoxicity
metabolites have been described. Garlic induces a strong and immune impairment.195 Certain phytochemicals
protective Th1 response while also eliminating the sus- due to their healing and antioxidant properties such as
ceptible as well as the drug-resistant strains. Silymarin, garlic, aqueous onion (Alium cepa) extract, silymarin,
extracted from the seeds of Sylibym marianum, induces and nanocurcumin lead to a significant reduction in liver
a remarkable expression of Th1 immune response related lesions induced by isoniazid, which has further been con-
cytokines both in treatment of drug-sensitive and - firmed by the lower expression level of liver enzymes such
resistant strains.193 Other examples of phytochemicals as alanine transaminase, alkaline phosphatase, and aspar-
with reported immunomodulatory effects are piperine, tate transaminase, which indicate improvement in the
an extract of chanca piedra (Phyllanthus niruri), extracts condition of ailing host liver as reported in the literature
of Rubiaceae species, allicin from garlic, curcumin from available for the medicinally important plants.196,197
turmeric, and gingerol from ginger. They have shown to act Therefore, as studied for some phytochemicals,
by restoring the Th1/Th2 balance, while acting as antioxi- the antimycobacterial action is mainly due to their
dants, anti-inflammatory agents, and immunomodulators immunomodulatory properties and their ability to prevent
and increasing the expression level of proinflamma- the adverse effects of antibiotic treatment. If more such
tory cytokines and NO.194 The mechanism of action of studies are conducted to further explore the bacterial
immunomodulators on the host system has been described clearing capacity of more phytochemicals and their
in Figure 5. Phytochemicals such as curcumin may be mechanism of action, this may contribute significantly
used as an alternative to steroids used in the management to the effectiveness of DOTS therapy, by reduction in
of inflammation during ATT based on the finding that the duration of TB treatment regimen, thus increasing
curcumin nanoparticles have been used restore the num- the effective bacterial clearance and simultaneously
ber and differentiation capacity of T-cells after isoniazid diminishing the chances of emergence of drug resistance
treatment, both in vitro and in mice model. It has also been in the bacteria. Any contribution these phytochemicals
reported to prevent “apoptosis” in immune cells, which is make may add to the improvement of an existing therapy
stimulated by antibiotics; by the activation of the caspase- or pave way for other novel therapies. This might be a
FATIMA et al. 507
big step in eradication of TB from the population. The 6 OUTLOOK AND FUTURE
effect of using these plant secondary metabolites as PERSPECTIVES
immunomodulators or as an adjunct therapy along with
the DOTS treatment has various consequences for the Despite highly active research on the development of
host. novel drugs against TBs we have quite a few drugs that
have been approved for the treatment of TB in the last
few decades,198 taking into consideration the fast emer-
5 CONCLUSION gence of drug-resistant strains. It has been reported that
the new anti-TB drugs in clinical trials such as Sequella
The phytochemicals derived from plant extracts are useful (SQ109), piperazine-benzothiazinone (PBTZ169), and ben-
not only in eliminating the bacteria but as discussed in the zothiazinones (BTZ043) have the pharmacophore of piper-
review may serve as prospective adjunct agents that help in ine, which is a phytochemical.199 Therefore, a plant-based
reducing the after-effects of the classical antimycobacterial drug molecule could be used as a research candidate for
drugs. These plant-derived products assist in reinstituting anti-TB treatment. Isoniazid despite having enumerable
the balanced level of the pro-inflammatory and anti- side effects cannot be replaced because of its effectiveness
inflammatory cytokine response of the host, which is and target binding specificity. However, any new drug that
disturbed by the bacteria upon infection. Furthermore, could reduce the inherent side effects of isoniazid when
studies on compounds with anti-MDR-TB and XDR-TB given in combination could revolutionize TB drug develop-
activity may contribute to the management of TB very sig- ment program. Moreover, phytochemical cotherapy along
nificantly as drug development against MDR- and XDR-TB with isoniazid and other anti-TB drugs leads us toward a
is the need of the hour, owing to its high prevalence and potent anti-TB drug development approach and is less time
difficult management. The plant-derived phytochemicals and expenditure demanding compared to searching of a
can also be given as personalized treatment to patients leading anti-TB drug candidate. These advantages pave a
suffering from other diseases along with TB; like silymarin promising future for the use of these phytochemicals in TB
can be given along with DOTS to a hepatitis patient who treatment.
gets infected with TB simultaneously. Many of these
phytochemicals and the compounds derived from them AC K N OW L E D G M E N T S
can be administered as inhalation therapy along with We would like to acknowledge financial support from the
DOTS to increase the effective drug concentrations within Department of Biotechnology (DBT), Department of Sci-
the lungs and thereby reduce the incidence of off-target ence and Technology (DST) and Science and Engineering
side-effects and systemic toxicity. Although, clinical trials Research Board (SERB), Department of Science and Tech-
involving combination use of some phytochemicals with nology (DST), Government of India. Dr Fatima is the recip-
the conventional ATT have shown to be very beneficial ient of DBT-RA Fellowship provided by DBT. Ms Kumari
in TB cure, but still the full potential of phytochemicals is the recipient of UGC-JRF Fellowship for doing her PhD.
still remains undeciphered. There are several limitations, Dr Dwivedi is the recipient of DST-INSPIRE Faculty Fel-
which prevent the successful use of these phytochemicals lowship (DST/INSPIRE/04/2014/002012) and Early Career
such as lack of knowledge about their interaction with Research Award (ND/DST/16/023) from SERB. We also
normal human diet and conventional drugs and less clarity would like to thank the institutional financial support
of their mechanism of action. However, these challenges from the International Centre for Genetic Engineering and
could be overcome by advancing multidisciplinary and Biotechnology (ICGEB), New Delhi, India.
high throughput research using bioinformatics, molecular
biology, and immunological approaches before it is used CONFLICT OF INTEREST
on animal models. The author’s confirm that there are no conflicts of interest.
Seeing the immense potential this therapy has, it could
definitely be recommended for use in the anti-TB drug reg- E T H I C S A P P R O VA L
imen in future to improve the effectiveness of the exist- No ethical approval was required for this study.
ing TB treatment procedures. In conclusion, we have pre-
sented many leads in this review article for mining of D A T A AVA I L A B I L I T Y S T A T E M E N T
new drug candidates as boosters of host-directed therapy We hereby declare that this review will be openly available
against the most deadly pathogen M. tuberculosis. for all.
508 FATIMA et al.
AU T H O R CO N T R I B U T I O N S 16. Lawal IO, Grierson DS, Afolayan AJ. Phytotherapeutic infor-

The authors confirm contribution to the paper as follows: mation on plants used for the treatment of tuberculosis in East-
study conception and design: Ved Prakash Dwivedi; data ern Cape Province, South Africa. Evid Based Complement Alter-
nat Med. 2014;2014:735423.
collection: Samreen Fatima, Anjna Kumari; analysis, inter-
17. Semenya SS, Maroyi A. Ethnobotanical survey of plants used
pretation, and critical revision for important intellectual
by Bapedi traditional healers to treat tuberculosis and its oppor-
content: Samreen Fatima; draft manuscript preparation: tunistic infections in the Limpopo Province, South Africa. S Afr
Samreen Fatima, Anjna Kumari. All authors reviewed the J Bot. 2019;122:401-421.
results and approved the final version of the manuscript. 18. Bunalema L, Obakiro S, Tabuti JR, Waako P. Knowledge on
plants used traditionally in the treatment of tuberculosis in
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Received: 9 November 2020 Revised: 8 April 2021 Accepted: 13 April 2021

Advances in adjunct therapy against tuberculosis:

Samreen Fatima Anjna Kumari Ved Prakash Dwivedi

Immunobiology Group, International

1 INTRODUCTION remains a threat with 10.5 million new cases reported

494 wileyonlinelibrary.com/journal/mco2 MedComm. 2021;2:494–513.

FIGURE 1 Tuberculosis treatment and associated side effects

FIGURE 2 The role of T cells in Tuberculosis pathogenesis and bacterial clearance

FIGURE 3 Evolution and the pillars of global TB eradication strategies

Tea is an extensively consumed drink worldwide. Among

TA B L E 1 List of phytochemicals having antimycobacterial properties

FIGURE 5 The mechanism of action of immunomodulators against TB

AU T H O R CO N T R I B U T I O N S 16. Lawal IO, Grierson DS, Afolayan AJ. Phytotherapeutic infor-

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