Planta Med 2013; 79 - PC9
DOI: 10.1055/s-0033-1348565

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

CGL Veale 1, RM Young 1, R Zoraghi 2, NE Reiner 2, RJ Andersen 3, MT Davies-Coleman 1
  • 1Department of Chemistry, Rhodes University, Grahamstown, South Africa
  • 2Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
  • 3Departments of Chemistry and of Earth and Ocean Sciences, University of British Columbia, Vancouver, BC, Canada

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.