A major mechanism of gram-negative bacterial resistance is the growing evolution and production of beta-lactamase enzymes (both serine- and metallo-active-site-based) that catalytically inactivate the superfamily of beta-lactam antibiotics. The recent spread of beta-lactamase-expressing "superbugs" is causing increased global alarm due to the high mortality associated with associated infections. To combat this threat, an iterative program of medicinal chemistry and biochemical/microbiological profiling was used to identify a broad spectrum inhibitor of both serine- and metallo-beta-lactamases, VNRX-5133, currently in clinical trials. The combination of VNRX-5133 with a known beta-lactam antibiotic has been shown in vitro and in vivo to rescue the latter's activity against key carbapenem-resistant enterobacteriaceae and Pseudomonas aeruginosa. This presentation will explore the medicinal chemistry optimization to VNRX-5133 from a narrow-spectrum, weakly active lead.

Discovery of VNRX-5133: A broad-spectrum serine- and metallo-beta-lactamase inhibitor (BLI) for carbapenem-resistant bacterial infections ("superbugs")

255th National Meeting (2018)

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