Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis.

Antimicrobial Agents and Chemotherapy
Chao ChenVéronique Dartois

Abstract

Mycobacterium tuberculosis kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several antituberculosis (anti-TB) drugs in vitro and in vivo This potentiation is widely attributed to inhibition of the efflux pumps of M. tuberculosis, resulting in intrabacterial drug accumulation. Here, we confirmed and quantified verapamil's synergy with several anti-TB drugs, including bedaquiline (BDQ) and clofazimine (CFZ), but found that the effect is not due to increased intrabacterial drug accumulation. We show that, consistent with its in vitro potentiating effects on anti-TB drugs that target or require oxidative phosphorylation, the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response similar to those seen with other membrane-active agents. We recapitulated these activities in vitro using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. We observed bactericidal activity against nonreplicating "persister" M. tuberculosis that was consistent with such a mechanism of action. In addition, ...Continue Reading

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Methods Mentioned

BETA
metabolomic profiling
confocal microscopy
reverse transcription-PCR
PCR

Software Mentioned

Analyst

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