Page 38 - Biennial Report 2018-20 Jun 2021

synthesis and transport pathways have been of interest from the standpoint of anti-bacterial
targets. A large family of multidrug resistance pumps called Resistance-Nodulation-Cell-Division
(RD) permeases is present in M. tuberculosis, represented by the subfamily named
Mycobacterial membrane protein Large (MmpL), which comprises of 13 members. Work from
Vivek Rao’s lab identified functions in stress mitigation for two lipid transporters belonging to
the MmpL family of M. tuberculosis. Gene deletion mutants of MmpL family genes were
generated in M. tuberculosis. MmpL11 was found to play an important role in bacterial
membrane stability in the presence of surface stress which translated to its relevance under lipid
rich conditions. It was found that fatty acid flux between bacterial cardiolipin and triglyceride is
altered in a M. tuberculosis strain deleted for Mmpl11. Host fatty acids were found to be the
source of membrane stress against which MmpL11 conferred resistance. MmpL6 was found to
play an important role in oxidative stress mitigation by Mtb. The absence of a functional Mmpl6
in modern lineages of M. tuberculosis was found to confer resistance to oxidative stress,
compounding to their ability to tolerate antibiotics. Interestingly, it was the ancient (south
Indian) lineage of M. tuberculosis strains found to be lacking the ability to synthesize an
important cell surface lipid, Sulpholipid SL1. A mutation in the gene PapA2 was found to result
in loss of ability to produce SL1. By solving the crystal structure of PapA2, the molecular
underpinnings of this link were established.

UNDERSTANDING INNATE IMMUNE RESPONSE IN TB PATHOGENESIS TOWARDS

DEVELOPMENT OF NOVEL HOST DIRECTED THERAPIES

Immune responses in TB can play a double-edged sword in pathogenesis. Vivek Rao’s lab focuses
on the Type I IFN response which is a known detrimental immune response during TB infection.
Through this work, they identified that the Type I IFN (IFNα/β) pathway is actively stimulated by
clinical Mtb strains to varying levels and is dependent on their ability to localize/ subvert the host
phagosomal-lysosomal degradation mechanisms. By using FDA approved anti-depressant
Sertraline to suppress this response, they have demonstrated antibiotic potentiation in cellular
models of infection against drug sensitive and drug tolerant M. tuberculosis. Initial experiments
have demonstrated increased survival of infected mice treated with this adjunct therapy. This
paves the way for drug repurposing towards potentially shorter TB therapy in preclinical models.

NOVEL DRUG FORMULATION AGAINST RESILIENT SKIN MICROBES

Acne is a skin condition caused by the accumulation of oil, dead skin cells and bacteria in pores
and follicles. Hormones, stress, diet and certain medications are some of the factors that
exacerbate acne. Although it is widely seen amongst teenagers, older people may also suffer
from acne. Rarely, it can be a persistent chronic condition that worsens inflammation, scars and
can cause distress to patients. Amongst the bacteria that reside in sebaceous glands and are
widely found in acne is Propionibacterium acnes (P. acnes). Individuals with acne symptoms
tend to harbor large numbers of P. acnes bacteria in their skin. Wockhardt Ltd has sponsored a
project at IGIB, to evaluate two molecules against 20 new Propionibacterium acnes strains and
5 methicillin-resistant Staphylococcus aureus (MRSA) strains. The expertise of Hemant Gautam
was invaluable in providing this support to the industrial partner through a consultancy project.

37