Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results.

ABSTRACT: The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar K(i) values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl)propylphosphonoacetamide (IC(50) = 8 nM, in cells), bound to CrtM.

SUBMITTER: Song Y 

PROVIDER: S-EPMC2753857 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature