Repurposing Vanoxerine as a new antimycobacterial drug and its impact on the mycobacterial membrane

Abstract

Mycobacterium tuberculosisis a deadly pathogen, currently the leading cause of death worldwide from a single infectious agent through tuberculosis infections. If the End TB 2030 strategy is to be achieved, additional drugs need to be identified and made available to supplement the current treatment regimen. In addition, drug resistance is a growing issue, leading to significantly lower treatment success rates, necessitating further drug development. Vanoxerine (GBR12909), a dopamine re-uptake inhibitor, was recently identified as having anti-mycobacterial activity. Repurposing vanoxerine or its analogues to treat tuberculosis infections may allow a faster route to clinical use than novel drug discovery. However, its effects on Mycobacteria were not well characterised. Herein, we report vanoxerine as a disruptor of the membrane potential, inhibiting mycobacterial efflux and survival, with an undetectable level of resistance. This study suggests a mechanism of action for vanoxerine, which will allow for its continued development and optimisation for pre-clinical testing.

Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition

“…We would like to thank Tanya Parish and Jessica Blair for their suggestions of experimental work to undertake. This work initially appeared as a pre-print on BioRxiv, (Kingdon et al, 2022(Kingdon et al, ). 10.3389/fmicb.2023 Frontiers in Microbiology 12 frontiersin.org…”