Multiple Bactericidal Mechanisms of the Zinc Ionophore PBT2
Nichaela Harbison-Price, Scott Ferguson, Adam Heikal, George Taiaroa, Kiel Hards, Yoshio Nakatani, David Rennison, Margaret A. Brimble, Ibrahim M. El‐Deeb, Lisa Bohlmann, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walker, Gregory M. Cook
Abstract
More antimicrobials are used in food-producing animals than in humans, and the extensive use of medically important human antimicrobials poses a significant public health threat in the face of rising antimicrobial resistance. Therefore, the elimination of antimicrobial crossover between human and veterinary medicine is of great interest. Unfortunately, the development of new antimicrobials is an expensive high-risk process fraught with difficulties. The repurposing of chemical agents provides a solution to this problem, and while many have not been originally developed as antimicrobials, they have been proven safe in clinical trials. PBT2, a zinc ionophore, is an experimental therapeutic that met safety criteria but failed efficacy checkpoints against both Alzheimer's and Huntington's diseases. It was recently found that PBT2 possessed potent antimicrobial activity, although the mechanism of bacterial cell death is unresolved. In this body of work, we show that PBT2 has multiple mechanisms of antimicrobial action, making the development of PBT2 resistance unlikely.