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https://doi.org/10.1128/AAC.02107-17
Title: | Verapamil targets membrane energetics in mycobacterium tuberculosis | Authors: | Chen, C Gardete, S Jansen, R.S Shetty, A Dick, T Rhee, K.Y Dartoisa, V |
Keywords: | ABC transporter subfamily B aminoglycoside amphophile antimycobacterial agent bacterial protein bedaquiline clofazimine ethambutol ethidium bromide hygromycin B isoniazid linezolid moxifloxacin octamer transcription factor pyrazinamide rifampicin streptomycin tuberculostatic agent verapamil bedaquiline calcium channel blocking agent clofazimine quinoline derivative tuberculostatic agent verapamil animal cell animal experiment animal model antibacterial activity area under the curve Article bacterial clearance bacterial membrane bactericidal activity concentration response controlled study drug accumulation drug disposition drug efficacy drug mechanism drug penetration drug potentiation drug targeting drug uptake fractional inhibitory concentration index gene expression human human cell in vitro study in vivo study macrophage membrane potential membrane vesicle minimum inhibitory concentration mouse Mycobacterium tuberculosis nonhuman oxidative phosphorylation phagocyte pharmacodynamics priority journal animal cell membrane drug effect drug potentiation female metabolism microbial sensitivity test Mycobacterium tuberculosis pathology Animals Antitubercular Agents Calcium Channel Blockers Cell Membrane Clofazimine Diarylquinolines Drug Synergism Female Humans Mice Microbial Sensitivity Tests Mycobacterium tuberculosis Verapamil |
Issue Date: | 2018 | Publisher: | American Society for Microbiology | Citation: | Chen, C, Gardete, S, Jansen, R.S, Shetty, A, Dick, T, Rhee, K.Y, Dartoisa, V (2018). Verapamil targets membrane energetics in mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 62 (5) : e02107-17. ScholarBank@NUS Repository. https://doi.org/10.1128/AAC.02107-17 | 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 “per-sister” 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. Copyright © 2018 Chen et al. | Source Title: | Antimicrobial Agents and Chemotherapy | URI: | https://scholarbank.nus.edu.sg/handle/10635/175116 | ISSN: | 0066-4804 | DOI: | 10.1128/AAC.02107-17 |
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