Synthetic Topsentin Analogues as Potent, Selective Inhibitors of Methicillin Resistant Staphylococcus Aureus Pyruvate Kinase

MRSA pyruvate kinase is an evolutionary conserved enzyme, responsible for catalysing the rate limiting final step in glycolysis. Sequence alignment and X-ray co-crystallography revealed amino acid sequence divergence from common human PK orthologs at the small interface, which is also the site of inhibitor binding. As part of an ongoing investigation of the MRSA inhibition activity and selectivity of marine bis-indole imidazole alkaloids we present the synthesis of dihalogenated analogues of the naturally occurring sponge metabolite topsentin, which display potent nanomolar activity against MRSA pyruvate kinase and 1000 – 10000 fold selectivity for the bacterial over human PK orthologs.