Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis

Mishra, Richa and Kohli, Sakshi and Malhotra, Nitish and Bandyopadhyay, Parijat and Mehta, Mansi and Munshi, MohamedHusen and Adiga, Vasista and Ahuja, Vijay Kamal and Shandil, Radha K and Rajmani, Raju S and Seshasayee, Aswin Sai Narain and Singh, Amit (2019) Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis. In: SCIENCE TRANSLATIONAL MEDICINE, 11 (518).

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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 post-chemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (C-max and AUC(last)) 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.

Item Type:	Journal Article
Publication:	SCIENCE TRANSLATIONAL MEDICINE
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Additional Information:	Copyright of this article belongs to AMER ASSOC ADVANCEMENT SCIENCE
Keywords:	PHAGOSOME-LYSOSOME FUSION; OXIDATIVE STRESS; EFFLUX PUMP; ANTITUBERCULOSIS DRUGS; TUBERCLE-BACILLI; NITRIC-OXIDE; ACIDIC PH; RESISTANCE; MACROPHAGES; CHLOROQUINE
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research
Date Deposited:	28 Feb 2020 09:37
Last Modified:	01 Mar 2020 17:12
URI:	http://eprints.iisc.ac.in/id/eprint/64058

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