Antibiotic resistance is an urgent medical threat as pathogenic bacteria continue to evolve and produce enzymes that render many current drugs ineffective. Common treatment options include β-lactam antibiotics that bind to a key enzyme in bacterial cell wall synthesis, penicillin binding protein, resulting in bacterial cell death. However, β-lactamases can hydrolyze these once-effective drugs, so inhibitors of β-lactamases were developed. Metallo-β-lactamases (MBLs) contain a catalytic zinc active site that is unaffected by standard β-lactamase inhibitors. We have synthesized and tested a prodrug as a strategy to selectively inhibit MBLs. This prodrug has a core that, once hydrolyzed by an MBL, inhibits the MBL. In order to increase strain specificity, an altered core structure was synthesized to increase its activity against drug-resistant strains, using a modular and efficient synthetic route. The improved strain selectivity of the prodrug is a promising strategy to increase drug efficacy, avoid off-target effects, and reduce the spread of resistance.

Preparation of later-generation prochelators to inhibit metallo-β-lactamase

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.