Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis.

Richa Mishra1,2, Sakshi Kohli1,2, Nitish Malhotra3, Parijat Bandyopadhyay1,2, Mansi Mehta1,2, MohamedHusen Munshi1,2, Vasista Adiga2, Vijay Kamal Ahuja4, Radha K Shandil4, Raju S Rajmani2, Aswin Sai Narain Seshasayee3, Amit Singh5

  1. Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
  2. Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560012, India.
  3. National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research (TIFR), Bangalore 560065, India.
  4. Foundation for Neglected Disease Research, Bangalore 560065, India.
  5. Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. asingh@iisc.ac.in.

Abstract

The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (C max and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.

Presented by Richa Mishra

Medicine, Immunology & MicrobiologyNicholas Liao2019-11 (Nov)