A major mechanism of gram-negative bacterial resistance is the growing evolution and production of beta-lactamase enzymes that catalytically inactivate the superfamily of beta-lactam antibiotics. The recent spread of carbapenem-inactivating “superbugs" is causing increased global alarm due to the high mortality associated with corresponding infections. While intravenous agents have advanced against such resistant bacteria, there are no orally bioavailable counterparts to allow hospital step-down and outpatient treatment.  To address this medical need, an iterative program of medicinal chemistry and biochemical/microbiological profiling was used to identify an orally bioavailable broad spectrum beta-lactamase inhibitor, VNRX-7145, which is currently in clinical development. The combination of VNRX-7145 with a known orally bioavailable beta-lactam antibiotic has been shown <i>in vitro </i>and<i> in vivo</i> to rescue the latter's activity against key carbapenem-resistant enterobacteriaceae. This presentation will explore the medicinal chemistry optimization to VNRX-7145 from less active, non-bioavailable lead compounds.

Discovery of VNRX-7145: A broad-spectrum orally bioavailable beta-lactamase inhibitor (BLI) for highly resistant bacterial infections ("superbugs")

2019 Spring National Meeting

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