Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis.

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Tuberculosis (TB), caused by *Mycobacterium tuberculosis*, is a leading cause of bacterial death.
• Emerging drug resistance makes TB increasingly difficult to treat.
• Verapamil, a calcium channel blocker, is known to potentiate anti-TB drugs.

Purpose of the Study:

• To elucidate the mechanism by which verapamil potentiates anti-TB drugs.
• To investigate the role of efflux pump inhibition versus membrane disruption.
• To explore verapamil's direct effects on *M. tuberculosis* membrane function and energetics.

Main Methods:

• In vitro synergy testing of verapamil with anti-TB drugs (e.g., bedaquiline, clofazimine).
• Measurement of intracellular drug accumulation in *M. tuberculosis*.
• Assessment of membrane function using inverted mycobacterial membrane vesicles.
• Evaluation of bactericidal activity against nonreplicating persister *M. tuberculosis*.
• Pharmacokinetic studies in mice to assess drug interactions.

Main Results:

• Verapamil synergizes with anti-TB drugs, but not via increased intracellular drug accumulation.
• Verapamil disrupts *M. tuberculosis* membrane function and induces a membrane stress response.
• Direct effects on membrane energetics were confirmed using inverted vesicles.
• Bactericidal activity against persister cells was observed.
• Verapamil boosted rifampin exposure in mice, suggesting a pharmacokinetic interaction.

Conclusions:

• Verapamil's potentiation of anti-TB drugs is primarily due to membrane disruption, not efflux pump inhibition.
• The bacterial membrane represents a novel pharmacologic target for anti-TB therapies.
• Verapamil's effects on membrane energetics and its pharmacokinetic interactions contribute to its therapeutic potentiation.