The growing threat of drug-resistant bacteria compels researchers to develop therapeutics with new modes of action. Copper has been used as an antimicrobial agent since ancient times, and compounds with copper-binding capabilities, such as pyrithione, have demonstrated promising antimicrobial activity. However, non-specific metal chelation leads to systemic disruption of metal homeostasis and undesired side effects, limiting the use of chelators as therapeutics. A way to direct metal chelation to the desired microenvironment is the use of prochelators. Prochelators are molecules that are unable to bind metals, but can be triggered by a stimulus, such as an enzyme, to release a chelating moiety. They remain inactive until triggered, allowing them to have activity only at the site of interest. Here, we report the antibacterial effects and investigate the role of copper in the mode of action of PcephPT, a prochelator triggered by β-lactamase to release pyrithione in the microenvironment of drug-resistant bacteria. We use biological methods, spectroscopy, and analytical techniques to understand the cellular responses to treatment, identify the speciation and potential binding partners of copper in the cell, and uncover changes in protein stability caused by treatment.

Understanding the role of copper in the mode of action of a β-lactamase-activated antibacterial prochelator

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.