Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Weill Cornell Medical College, Weill Department of Medicine, New York, New York, USA.
Antimicrob Agents Chemother. 2018 Apr 26;62(5). doi: 10.1128/AAC.02107-17. Print 2018 May.
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 and This potentiation is widely attributed to inhibition of the efflux pumps of , 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 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 using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. We observed bactericidal activity against nonreplicating "persister" 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 and and highlight a previously unrecognized role for the membrane of as a pharmacologic target.
导致的死亡人数超过其他任何细菌病原体，并且由于耐药性的出现，越来越难以治疗。维拉帕米是一种获得 FDA 批准的钙通道阻滞剂，能够增强几种抗结核（抗 TB）药物的作用，这种增强作用广泛归因于抑制 的外排泵，导致细菌内药物积累。在这里，我们证实并量化了维拉帕米与几种抗结核药物（包括贝达喹啉（BDQ）和氯法齐明（CFZ））的协同作用，但发现这种作用不是由于细菌内药物积累增加所致。我们表明，与靶向或需要氧化磷酸化的抗结核药物一样，阳离子两亲性维拉帕米破坏膜功能并诱导类似于其他膜活性剂的膜应激反应。我们使用倒置分枝杆菌膜囊泡再现了这些活性，表明维拉帕米对膜能量学有直接影响。我们观察到对非复制“持久菌”的杀菌活性，这与这种作用机制一致。此外，我们证明了一种药代动力学相互作用，即人体等效剂量的维拉帕米会使利福平在小鼠体内的暴露增加，这为观察到的维拉帕米在接受一线药物治疗的小鼠中缩短治疗时间的作用提供了潜在解释。因此，我们的发现阐明了维拉帕米增强抗结核药物的作用机制，并强调了 的膜作为药理学靶标的先前未被认识到的作用。
