TitleTargeting redox heterogeneity to counteract drug tolerance in replicating .
Publication TypeJournal Article
Year of Publication2019
AuthorsMishra R, Kohli S, Malhotra N, Bandyopadhyay P, Mehta M, Munshi MH, Adiga V, Ahuja VKamal, Shandil RK, Rajmani RS, Seshasayee ASai Narain, Singh A
JournalSci Transl Med
Date Published2019 Nov 13

The capacity of () to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in 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 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 (HS) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when 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 , ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ ( and AUC) 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 and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.

Alternate JournalSci Transl Med
PubMed ID31723039