Title | Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Chen C, Gardete S, Jansen RSander, Shetty A, Dick T, Rhee KY, Dartois V |
Journal | Antimicrob Agents Chemother |
Volume | 62 |
Issue | 5 |
Date Published | 2018 05 |
ISSN | 1098-6596 |
Keywords | Animals, Antitubercular Agents, Calcium Channel Blockers, Cell Membrane, Clofazimine, Diarylquinolines, Drug Synergism, Female, Humans, Mice, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Verapamil |
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, we demonstrated a pharmacokinetic interaction whereby human-equivalent doses of verapamil caused a boost of rifampin exposure in mice, providing a potential explanation for the observed treatment-shortening effect of verapamil in mice receiving first-line drugs. Our findings thus elucidate the mechanistic basis for verapamil's potentiation of anti-TB drugs in vitro and in vivo and highlight a previously unrecognized role for the membrane of M. tuberculosis as a pharmacologic target. |
DOI | 10.1128/AAC.02107-17 |
Alternate Journal | Antimicrob Agents Chemother |
PubMed ID | 29463541 |
PubMed Central ID | PMC5923092 |
Grant List | R01 AI106398 / AI / NIAID NIH HHS / United States S10 OD023524 / OD / NIH HHS / United States U19 AI111143 / AI / NIAID NIH HHS / United States |