Research ArticleTuberculosis

Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis

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Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaaw6635
DOI: 10.1126/scitranslmed.aaw6635

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Antibiotic redox-based redux

Phagosomal pH and redox heterogeneity in Mycobacterium tuberculosis (Mtb) can promote tolerance of the bacterium to antibiotics. Mishra et al. found that the approved antimalarial drug chloroquine inhibited this acidification and resulted in altered redox metabolism and improved susceptibility of Mtb to first-line antituberculosis drugs, particularly isoniazid, in infected macrophages in vitro. Coadministration of chloroquine improved isoniazid treatment outcomes in both mouse and guinea pig models of Mtb infection. This work suggests the repurposing of chloroquine to potentiate and possibly shorten antibiotic treatment of tuberculosis.

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 (Cmax 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.

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