Verapamil increases the bioavailability and efficacy of bedaquiline but not clofazimine in a murine model of tuberculosis

Jian Xu, Rokeya Tasneen, Charles A. Peloquin, Deepak V. Almeida, Si Yang Li, Kala Barnes-Boyle, Yu Lu, Eric Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine, and other drugs against Mycobacterium tuberculosis, has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and clofazimine against M. tuberculosis clinical isolates, including those harboring rv0678 mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity in vivo, but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.

Original languageEnglish (US)
Article numbere01692
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Bedaquiline
  • Bioavailability
  • Efflux pump
  • Mycobacterium tuberculosis
  • Verapamil

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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