Please use this identifier to cite or link to this item:
https://doi.org/10.1128/AAC.02107-17
DC Field | Value | |
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dc.title | Verapamil targets membrane energetics in mycobacterium tuberculosis | |
dc.contributor.author | Chen, C | |
dc.contributor.author | Gardete, S | |
dc.contributor.author | Jansen, R.S | |
dc.contributor.author | Shetty, A | |
dc.contributor.author | Dick, T | |
dc.contributor.author | Rhee, K.Y | |
dc.contributor.author | Dartoisa, V | |
dc.date.accessioned | 2020-09-09T04:09:10Z | |
dc.date.available | 2020-09-09T04:09:10Z | |
dc.date.issued | 2018 | |
dc.identifier.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 | |
dc.identifier.issn | 0066-4804 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/175116 | |
dc.description.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. | |
dc.publisher | American Society for Microbiology | |
dc.source | Unpaywall 20200831 | |
dc.subject | ABC transporter subfamily B | |
dc.subject | aminoglycoside | |
dc.subject | amphophile | |
dc.subject | antimycobacterial agent | |
dc.subject | bacterial protein | |
dc.subject | bedaquiline | |
dc.subject | clofazimine | |
dc.subject | ethambutol | |
dc.subject | ethidium bromide | |
dc.subject | hygromycin B | |
dc.subject | isoniazid | |
dc.subject | linezolid | |
dc.subject | moxifloxacin | |
dc.subject | octamer transcription factor | |
dc.subject | pyrazinamide | |
dc.subject | rifampicin | |
dc.subject | streptomycin | |
dc.subject | tuberculostatic agent | |
dc.subject | verapamil | |
dc.subject | bedaquiline | |
dc.subject | calcium channel blocking agent | |
dc.subject | clofazimine | |
dc.subject | quinoline derivative | |
dc.subject | tuberculostatic agent | |
dc.subject | verapamil | |
dc.subject | animal cell | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | antibacterial activity | |
dc.subject | area under the curve | |
dc.subject | Article | |
dc.subject | bacterial clearance | |
dc.subject | bacterial membrane | |
dc.subject | bactericidal activity | |
dc.subject | concentration response | |
dc.subject | controlled study | |
dc.subject | drug accumulation | |
dc.subject | drug disposition | |
dc.subject | drug efficacy | |
dc.subject | drug mechanism | |
dc.subject | drug penetration | |
dc.subject | drug potentiation | |
dc.subject | drug targeting | |
dc.subject | drug uptake | |
dc.subject | fractional inhibitory concentration index | |
dc.subject | gene expression | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | in vitro study | |
dc.subject | in vivo study | |
dc.subject | macrophage | |
dc.subject | membrane potential | |
dc.subject | membrane vesicle | |
dc.subject | minimum inhibitory concentration | |
dc.subject | mouse | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | nonhuman | |
dc.subject | oxidative phosphorylation | |
dc.subject | phagocyte | |
dc.subject | pharmacodynamics | |
dc.subject | priority journal | |
dc.subject | animal | |
dc.subject | cell membrane | |
dc.subject | drug effect | |
dc.subject | drug potentiation | |
dc.subject | female | |
dc.subject | metabolism | |
dc.subject | microbial sensitivity test | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | pathology | |
dc.subject | Animals | |
dc.subject | Antitubercular Agents | |
dc.subject | Calcium Channel Blockers | |
dc.subject | Cell Membrane | |
dc.subject | Clofazimine | |
dc.subject | Diarylquinolines | |
dc.subject | Drug Synergism | |
dc.subject | Female | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Microbial Sensitivity Tests | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | Verapamil | |
dc.type | Article | |
dc.contributor.department | MEDICINE | |
dc.contributor.department | MICROBIOLOGY AND IMMUNOLOGY | |
dc.description.doi | 10.1128/AAC.02107-17 | |
dc.description.sourcetitle | Antimicrobial Agents and Chemotherapy | |
dc.description.volume | 62 | |
dc.description.issue | 5 | |
dc.description.page | e02107-17 | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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