Advances in Bioscience and Biotechnology, 2013, 4, 10-14 ABB Published Online November 2013 (
Antioxidants: Friend or foe for tuberculosis patients
Rajasri Bhattacharyya1, Dibyajyoti Banerjee2*
1Department of Biotechnology, Maharishi Markandeshwar Univer sity, Mullana, Ambala, India
2Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh,
Email: *
Received 22 August 2013; revised 22 September 2013; accepted 15 October 2013
Copyright © 2013 Rajasri Bhattacharyya, Dibyajyoti Banerjee. This is an open access article distributed under the Creative Com-
mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.
Respiratory burst induced bacteria killing by oxi-
dants are important mechanism of host defence.
However, it is impaired in tuberculosis due to inhibi-
tion of respiratory burst by Mycobacterial factors.
Antioxidants are compounds that cause chelation of
reactive oxygen species. So, antioxidants are expected
to play a negative role in the management of active
tuberculosis. But, oxidative st ress is a proved fact that
invariably happens in tuberculosis patients which is
known to cause immunosuppression. Immunosup-
pression in turn is expected to augment tuberculosis.
Hence, antioxidant supplementation is expected to
benefit tuberculosis patients by minimising oxidative
stress induced immunosuppression. Therefore, the
role of antioxidants in tuberculosis appears to be
paradoxical and urgent. Understanding of the role of
antioxidant supplementation in tuberculosis is war-
ranted. It is in this context that we have reviewed the
recent literature and addressed the problem for its
Keywords: Tubercul osi s; A nt i oxi dants; Reacti ve
Oxygen Species; Clinical Trial; Mycobacterial
Antioxidants are among the most popular health-pro-
tecting products, sold worldwide with out prescription . At
the present moment, there is majority opinion that anti-
oxidants are good for human health but very recently
some researchers are in the opinion that it may not be
good for hu man health un iversall y [1].
In case of infections intracellular generation of ROS/
RNS plays an important role in pathogen clearance.
Phagocytosis is the process by which all pathogens are
engulfed by the macrophages. In the process of phago-
cytosis, a membrane bound vesicle is formed containing
the pathogen. This membrane bound vesicle, is popularly
known as phagosome. Phagosome generally contains
various subunits of NADPH oxidase, the respiratory
burst enzyme (that generates superoxide), iNOS (that
generates peroxynitrite), and many other proteins that
generally undergoes a maturation process by which in-
ternalized particles (such as bacteria and dead cells etc.)
are trafficked into a series of increasingly acidified mem-
brane-bound structures (endosomes, lysosomes), leading
to particle degradation [2 ,3]. It is also now proved that if
the phagosomal ROS is not produced or less produced
the host becomes susceptible to intracellular infections.
The classical example of the above statement is chronic
granulomatous disease which is characterized by dimin-
ished capacity of intracellular ROS production lead ing to
tubercul osi s very often [4].
The role of extracellular antioxidants may be critical
in functioning of intracellular ROS. It is expected that
the available extracellular antioxidant will percolate in-
side the cell and neutralize the nascent ROS. In that case
antioxidants should be harmful in the scenario of active
infections. However, some antioxidants behave as pro-
oxidants in specialized situations. Below an example is
elaborated for explanation of the above mentioned fact.
α-tocopherol (α-TC, Vitamin E) produces α-toco-
pheroxyl radical when it reacts with reactive species su ch
as peroxynitrite [5] or superoxide [6]. α-TC radical is
then recycled to α-TC by other antioxidants such as
ascorbic acid (Vita min C) and glutathione [7-9]. As soon
as ascorbic acid recycles Vitamin E, it is transformed to
the ascorbyl radical, which has a lower reactivity than
α-TC radical [7]. α-TC radical is also recycled to α-TC
by β-carotene [9,10]. So, for proper antioxidant effect
Vitamin E should be administered with another antioxi-
dant and excess amount of vitamin E may be pro-oxidant
*Corresponding a uthor.
R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14 11
per se. Therefore, it is important to und erstand the role of
vitamin E in various concentrations in presence and ab-
sence of other antioxidants, on the re-ox capacity of in-
tracellular nascent ROS. Similar examples may be cited
with all the commonly used antioxidants and the role of
commonly used antioxidants in intracellular ROS pro-
duction/fu nct i o n is unclear a s on dat e. Such knowledge is
important keeping in mind the prevalence of the infec-
tious diseases and the consumption habit of antioxidants
of public at large. In this article the same will be at-
tempted to be reviewed in the context of tuberculosis.
Mycobacterium tuberculosis
Mycobacterium tuberculosis is engulfed by host macro-
phages. It resides inside a stable phagosome which does
not fuse with lysosome for effective bacterial killing.
Such maturation arrest of phagosomes containing My-
cobacterium tuberculosis is thought due to defective re-
cruitment of rab proteins in such phagosomes [11]. My-
cobacterial factor like secreted acid phosphatase is also
thought to be important for inhibition of phagolysosome
biogenesis [12]. As a result the tuberculosis bacterium
resides inside the phagosome without experiencing the
adverse environment produced by lysosomal acid hy-
dr olases. More over Mycobacterium containing phagosom e
recruits cellular iron into the phagosome which is util-
ized for bacterial sustenance [13]. The phagosome is
supposed to posses subunits of NAD PH oxidase, the key
enzyme for respiratory burst which in turn is expected to
generate supero xide. F urther m yelopero xidase i n phagos ome
is known to form hypohalites. Both superoxide and hy-
pohalites are known agents that kill intraphagosomal
parasites. Inducible nitric oxide synthase is also known
to be recruited in phagosomes which generates peroxyni-
trite, the toxic free radical and mediates bacterial killing.
However, Mycobacterial factors are known to inhibit the
function of inducible nitric oxide synthase and NADPH
oxidase and thus less oxidants are produced in Myco-
bacterium tuberculosis containing phagosome, making
the phagosomal pathogen to stay inside a protective
cover [14, 1 5].
Mycobacterium tuberculosis is an intracellular pathogen
and currently infected more than one third of global
population. Like all intracellular pathogens it resides
successfully inside phagosome of macrophages. Myco-
bacterial factors inhibit phagosome maturation so that the
intraphagosomal bacterium is not assaulted by lyso somal
hydrolases [12]. Various bacterial antioxidants are also
proved to counter phagosomal respiratory burst causing
safe stay of the tuberculosis bacterium inside the pha-
gosome [16-18]. In case of atypical Mycobacterium spe-
cies bacterial antioxidants are thought to modulate host
derived oxidative killing mechanisms [19]. In Mycobac-
terium species new antioxidant mechanisms that protect
the bacterium from the phagosomal respiratory burst is
an established phenomenon [20,21]. Even recombinant
BCG over-expressed with superoxide dismutase A con-
fers less protection for development of tuberculosis [22].
Pathogen derived antioxidant mediated escape from pha-
gosomal oxidative burst is not unique for tuberculosis
bacterium and proved to be true in other successful in-
tracellular pathogen as well [23,24]. Host derived anti-
oxidants are also recently proved to be beneficial for
persistence of intracellular pathogen s [25]. Therefore it is
appearing that availability of antioxidants at the pha-
gosome play a negative role for the host in cases of ac-
tive tuberculosis infection.
On the other hand antioxidants like N-acetyl cysteine
is shown to inhibit growth of tuberculosis bacteria inside
tubercular abscess [26]. Such observations are also con-
firmed with other antioxidants like manganese (II) meso-
tetrakis-(N-methylpyridinium-2-yl) porphyrin [27]. Fur-
ther, glutathione is known to modulate the T cell medi-
ated immune response in a manner that reduces the in-
tracellular stability of the tuberculosis bacterium [28].
This fact is observed to be true for many other intracel-
lular infection and so may be considered as a general
phenomenon [29]. Extra cellular superoxide dismutase is
shown to augment phagocytic killing of bacteria [30].
There is evidence in in-vivo studies that control of oxi-
dative stress by supply of antioxidants is beneficial for
prevention and treatment of tuberculosis [31]. In living
human tuberculosis patients oxidative stress is also prov ed
beyond any doubt [32]. The activities of antioxidant en-
zymes are observed to be comparatively less in blood
samples in subjects suffering from active tuberculosis
along with corroborative increase in concentration of pro-
tein carbonyl [33].
Therefore antioxidants if neutralize the phagosomal
oxidants has the chance to augment active form of tu-
berculosis. In other hand if antioxidants are expected to
modulate the immune response to combat intracellular
infection then it may act as a preventive armor for tu-
berculosis. In the context of tuberculosis supplementa-
tion of antioxidants will play beneficial role or not needs
a solution of the paradoxical evidences so far accumu-
Clinical effect of vitamin E is not observed in recipients
who consume less vitamin C containing diet [34]. It has
been observed that vitamin E supp lementation transien tly
Copyright © 2013 SciRes. OPEN ACCESS
R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14
increases the risk of active tuberculosis in heavy smokers
if co-supplemented with vitamin C [35]. Similar conclu-
sions are arrived in clinical cases of pneumonia [36].
Therefore vitamin C and vitamin E co-supplementation
may be harmful for any infectious disease including tu-
berculosis. It is possible that vitamin C neutralizes to-
copheryl radical that may have microbiocidal role.
Oxidative stress is a proved fact associated with tu-
berculosis [31,32]. Oxidative stress is a phenomenon that
may cause immunosuppression [37]. Oxidative stress
results into defective T cell mediated immunity [38] which
in turn may accelerate tuberculosis infection. Therefore
antioxidant supplementation in tuberculosis patients alo ng
with recommended chemotherapy may help to combat
the oxidative stress mediated defective cell mediated
immunity. In the context of tuberculosis management,
treatment of the cause of the disease is important since
now it is a recognized fact that in the scenario of oxida-
tive stress the management must address the cause of
genesis of the primary disease [39]. However both en-
dogenous and exogenous antioxidants are observed to be
protective against antitubercular drug induced toxicity
[40,41]. Therefore co administration of antioxidants and
anti-tubercular drugs has the potential to serve benefit to
tuberculosis patients for multiple causes. But blind sup-
plementation of antioxidants with anti-tubercular drugs
in tuberculosis patients may cause more harm than bene-
fit. We believe that if oxidative stress develops in a par-
ticular case of tuberculosis appropriate antioxidant sup-
plementation along with antitubercular therapy will ac-
celerate the healing process. Therefore clinical trials in
this direction are warranted to document objective data
to formulate rational antioxidant combination therapy as
an adjunct to antitubercular drug therapy in proved cases
of tuberculosis.
DB acknowledges Department of Biotechnology, Govt. of India for
financial assistance.
[1] Villanueva, C. and Kross, R.D. (2012) Antioxidant in-
duced stress. International Journal of Molecular Science,
13, 2091-2109.
[2] Kinchen, J.M. and Ravichandran, K.S. (2008) Phagosome
maturation: Going through the acid test. Nature Reviews
Molecular Cell Biology, 9, 781-795.
[3] Miller, B.H., Fratti, R.A., Poschet, J.F., et al. (2004)
Mycobacteria inhibit nitric oxide synthase recruitment to
phagosomes during macrophage infection. Infection and
Immunity, 72, 2872-2878.
[4] Lee, P.P., Chan, K.W., Jiang, L., et al. (2008) Suscepti-
bility to mycobacterial infections in children with X-
linked chronic granulomatous disease: A review of 17 pa-
tients living in a region endemic for tuberculosis. The Pe-
diatric Infectious Disease Journal, 27, 224-230.
[5] Botti, H., Batthyány, C., Trostchansky, A., et al. (2004)
Peroxynitrite-mediated alpha-tocopherol oxidation in low-
density lipoprotein: A mechanistic approach. Free Radi-
cal Biology and Medicine, 36, 152-162.
[6] Maguire, J.J., Wilson, D.S. and Packer, L. (1989) Mito-
chondrial electron transport-linked tocopheroxyl radical
reduction. Journal of Biological Chemistry, 264, 21462-
[7] Damiani, E., Astolfi, P., Carloni, P., Stipa, P. and Greci,
L. (2008) Antioxidants: How they work. In: Valacchi, G.
and Davis, P.A., Eds., Oxidants in Biology, Springer Sci-
ence Buisness Media, New York, 251-266.
[8] Duracková, Z. (2008) Oxidants, antioxidants and oxida-
tive stress. In: Gvozdjáková, A., Ed., Mitochondrial Me-
dicine, Springer Science Business Media, New York, 19-
[9] Liu, C., Russell, R.M. and Wang, X.D. (2004) Alpha-
tocopherol and ascorbic acid decrease the production of
beta-apo-carotenals and increase the formation of reti-
noids from beta-carotene in the lung tissues of cigarette
smoke-exposed ferrets in vitro. Journal of Nutrition, 134,
[10] Yeum, K.J., Aldini, G., Russell, R.M. and Krinsky, N.I.
(2009) Carotenoids, Vol. 5, Birkhäuser Verlag, Basel, 235-
[11] Vergne, I., Chua, J. and Deretic, V. (2003) Mycobacte-
rium tuberculosis phagosome maturation arrest: Selective
targeting of PI3P-dependent membrane trafficking. Tra-
ffic, 4, 600-606.
[12] Puri, R.V., Reddy, P.V. and Tyagi, A.K. (2013) Secreted
acid phosphatase (SapM) of mycobacterium tuberculosis
eIs indispensable for arresting phagosomal maturation
and growth of the pathogen in guinea pig tissues. PLoS
One, 8, e70514.
[13] Luo, M., Fadeev, E.A. and Groves, J.T. (2005) Mycobac-
tin-mediated iron acquisition within macrophages. Nature
Chemical Biology, 1, 149-153.
[14] Banerjee, D., Bhattacharyya, R., Kaul, D. and Sharma, P.
(2011) Diabetes and tuberculosis: Analysis of a paradox.
Advance in Clinical Chemistry, 53, 139-153.
[15] Bhattacharyya, R. and Banerjee, D. (2011) Glycation of
calmodulin binding domain of iNOS may increase the
chance of occurrence of tuberculosis in chronic diabetic
state. Bioinformation, 7, 324-327.
[16] Trivedi, A., Singh, N., Bhat, S.A., Gupta, P. and Kumar,
A. (2012) Redox biology of tuberculosis pathogenesis.
Copyright © 2013 SciRes. OPEN ACCESS
R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14 13
Advances in Microbial Physiology, 60, 263-324.
[17] Braunstein, M., Espinosa , B.J., Chan, J., Beli sle, J.T. and
Jacobs Jr., W.R. (2003) SecA2 functions in the secretion
of superoxide dismutase A and in the virulence of Myco-
bacterium tuberculosis. Molecular Microbiology, 48, 453-
[18] Piddington, D.L., Fang, F.C., Laessig, T., Cooper, A.M.,
Orme, I.M. and Buchmeier, N.A. (2001) Cu, Zn super-
oxide dismutase of Mycobacterium tuberculosis contrib.-
utes to survival in activated macrophages that are gener-
ating an oxidative burst. Infection and Immunity, 69,
[19] Sao Emani, C., Williams, M.J., Wiid, I.J., Hiten, N.F.,
Viljoen, A.J., Pietersen, R.D., van Helden, P.D. and Ba ke r,
B. (2013) Ergothioneine is a secreted antioxidant in My-
cobacterium smegmatis. Antimicrobial Agents and Che-
motherapy, 57, 3202-3207.
[20] Gurumurthy, M., Rao, M., Mukherjee, T., Rao, S.P., Bo-
shoff, H.I., Dick, T., Barry, C.E. 3rd and Manjunat ha, U . H.
(2013) A novel F(420)-dependent anti-oxidant mecha-
nism protects Mycobacterium tuberculosis against oxida-
tive stress and bactericidal agents. Molecular Microbiol-
ogy, 87, 744-755. http :// dx. doi .org/10 .1111/mmi.12127
[21] Saikolappan, S., Das, K., Sasindran, S.J., Jagannath, C.
and Dhandayuthapani, S. (2011) OsmC proteins of My-
cobacterium tuberculosis and Mycobacterium smegmatis
protect against organic hydroperoxide stress. Tuberculo-
sis, 91, S119-S127.
[22] Jain, R., Dey, B., Khera, A., Srivastav, P., Gupta, U.D.,
Katoch, V.M., Ramanathan, V.D. and Tyagi, A.K. (2011)
Over-expression of superoxide dismutase obliterates the
protective effect of BCG against tuberculosis by modu-
lating innate and adaptive immune responses. Vaccine, 29,
[23] De Groote, M.A., Ochsner, U.A., Shiloh, M.U., et al.
(1997) Periplasmic superoxide dismutase protects Sal-
monella from products of phagocyte NADPH-oxidase
and nitric oxide synthase. Proceedings of the National
Academy of Science of United States of America, 94,
[24] Frohner, I.E., Bourgeois, C., Yatsyk, K., Majer, O. and
Kuchler, K. (2009) Candida albicans cell surface super-
oxide dismutases degrade host-derived reactive oxygen
species to escape innate immune surveillance. Molecular
Microbiology, 71, 240-252.
http://dx.doi. org/10. 1111/j.1365-2958.2008.06528.x
[25] Youseff, B.H., Holbrook, E.D., Smolnycki, K.A. and
Rappleye, C.A. (2012) Extracellular superoxide dismu-
tase protects Histoplasma yeast cells from host-derived
oxidative stress. PLoS Pathogens, 8, e1002713.
[26] Oberley-Deegan, R.E., Rebits, B.W., Weaver, M.R., et al.
(2010) An oxidative environment promotes growth of
Mycobacterium abscessus. Free Radical Biology and Me-
dicine, 49, 1666-1673.
[27] Oberley-Deegan, R.E., Lee, Y.M., Morey, G.E., Cook,
D.M., Chan, E.D. and Crapo, J.D. (2009) The antioxidant
mimetic, MnTE-2-PyP, reduces intracellular growth of
Mycobacterium abscessus. American Journal of Respira-
tory Cell and Molecular Biology, 41, 170-178.
[28] Guerra, C., Morris, D., Sipin, A., et al. (2011) Gluta-
thione and adaptive immune responses against Mycobac-
terium tuberculosis infection in healthy and HIV infected
individuals. PLoS One, 6, e28378.
[29] Morris, D., Khurasany, M., Nguyen, T., et al. (2013) Glu-
tathione and infection. Biochimica et Biophysica Acta,
1830, 3329-3349.
[30] Manni, M.L., Tomai, L.P., Norris, C.A., et al. (2011) Ex-
tracellular superoxide dismutase in macrophages aug-
ments bacterial killing by promoting phagocytosis. The
American Journal of Pathology, 178, 2752-2759.
[31] Palanisamy, G.S., Kirk, N.M., Ackart, D.F., et al. (2011)
Evidence for oxidative stress and defective antioxidant
response in guinea pigs with tuberculosis. PLoS One, 6,
[32] Dalvi, S.M., Patil, V.W., Ramraje, N.N., Phadtare, J.M.
and Gujarathi, S.U. (2013) Nitric oxide, carbonyl protein,
lipid peroxidation and correlation between antioxidant
vitamins in different categories of pulmonary and extra
pulmonary tuberculosis. The Malaysian Journal of Medi-
cal Sciences, 20, 21-30.
[33] Dalvi, S.M., Patil, V.W. and Ramraje, N.N. (2012) The
roles of glutathione, glutathione peroxidase, glutathione
reductase and the carbonyl protein in pulmonary and ex-
tra pulmonary tuberculosis. Journal of Clinical and Di-
agnostic Research, 6, 1462-1465.
[34] Hemilä, H. and Kaprio J. (2009) Modification of the ef-
fect of vitamin E supplementation on the mortality of
male smokers by age and dietary vitamin C. American
Journal of Epidemiology, 169, 946-953.
[35] Hemilä, H. and Kaprio, J. (2008) Vitamin E supplemen-
tation may transiently increase tuberculosis risk in males
who smoke heavily and have high dietary vitamin C in-
take. The British Journal of Nutrition, 100, 896-902.
[36] Hemilä, H. and Kaprio, J. (2008) Vitamin E supplemen-
tation and pneumonia risk in males who initiated smoking
at an early age: Effect modification by body weight and
dietary vitamin C. Nutrition Journal, 7, 33.
[37] Zhang, Z.W., Wang, Q.H., Zhang, J.L., Li, S., Wang, X.L.
and Xu, S.W. (2012) Effects of oxidative stress on im-
muno-suppression induced by selenium deficiency in
chickens. Biological Trace Element Research, 149, 352-
[38] Efimova, O., Szankasi, P. and Kelley, T.W. (2011) Ncf1
Copyright © 2013 SciRes. OPEN ACCESS
R. Bhattacharyya, D. Banerjee / Advances in Bioscience and Biotechnology 4 (2013) 10-14
Copyright © 2013 SciRes.
(p47phox) is essential for direct regulatory T cell me-
diated suppression of CD4+ effector T cells. PLoS One, 6,
[39] Naviaux, R.K. (2012) Oxidative shielding or oxidative
stress? The Journal of Pharmacology and Experimental
Therapeutics, 342, 608-618.
[40] Lian, Y., Zhao, J. and Xu, P. (2013) Protective effects of
metallothionein on isoniazid and rifampicin-induced he-
patotoxicity in mice. PLoS One, 8, e72058.
[41] Ergul, Y., Erkan, T., Uzun, H., Genc, H., Altug, T. and
Erginoz, E. (2010) Effect of vitamin C on oxidative liver
injury due to isoniazid in rats. Pediatrics International,
52, 69-74.
http://dx.doi. org/10. 1111/j.1442-200X.2009.02891.x