LpxC is a zinc metalloenzyme that catalyses the committed step in synthesis of the bacterial cell wall. Previous studies by other companies have identified inhibitors of the enzyme based on a hydroxamic acid as the zinc chelating agent. Some have entered clinical trials as antibiotics, but not progressed, possibly because of the liabilities of off-target effects and lack of tolerability associated with the hydroxamic acids.
A collaboration between Vernalis Research and Taisho Pharmaceuticals used fragment and structure-based discovery methods to identify novel zinc-chelators. This is described in a recent paper in the Journal of Medicinal Chemistry (vol 63, p 14805) with the most advance lead showing good antibacterial activity on cells. Taisho Pharmaceuticals have subsequently optimised the series to a compound which has been widely profiled for antibacterial activity and considered for clinical development.
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