Targeting redox heterogeneity to counteract drug tolerance in replicating .
|Title||Targeting redox heterogeneity to counteract drug tolerance in replicating .|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Mishra R, Kohli S, Malhotra N, Bandyopadhyay P, Mehta M, Munshi MH, Adiga V, Ahuja VKamal, Shandil RK, Rajmani RS, Seshasayee ASai Narain, Singh A|
|Journal||Sci Transl Med|
|Date Published||2019 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 Journal||Sci Transl Med|