Here we describe recent efforts aimed at finding new anti-bacterial leads that target enzymes involved in isoprenoid biosynthesis. These enzymes include undecaprenyl diphosphate synthase (UPPS), essential for bacterial cell wall peptidoglycan formation, and dehydrosqualene synthase (CrtM), used in formation of the Staphylococcus aureus virulence factor staphyloxanthin, which promotes resistance to oxidant-based host defenses. Several leads were developed based on the observation that most HIV-integrase inhibitors bind to a Mg2+/Asp rich cluster in the active site, and a similar Mg2+/Asp is present in the UPPS and CrtM active sites, while other inhibitors were discovered via in silico high throughput screening. We obtained 6 X-ray structures of several such compounds bound to CrtM and UPPS. These leads can act in a direct manner, killing cells; they can target virulence; plus, they can stimulate innate immunity (via NET formation), and in some cases they have multiple effects.

Discovery of antibacterial leads targeting isoprenoid biosynthesis: A knowledge and structure-based approach

243rd National Meeting (2012)

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