title: 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. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.
authors.affiliation: Department of Chemistry and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Liu
authors.forename: Fu-Yang
authors.initials: FY
authors.lastname: Lin
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.forename: Mary
authors.initials: M
authors.lastname: Hensler
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.forename: Wen-Yih
authors.initials: WY
authors.lastname: Jeng
authors.forename: Jennifer
authors.initials: J
authors.lastname: Low
authors.forename: George Y
authors.initials: GY
authors.lastname: Liu
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D024341:Xanthophylls / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D037521:Virulence Factors; D024341:Xanthophylls; C063084:phosphonoacetamide; C031841:staphyloxanthin; C091056:CrtM protein, Staphylococcus aureus; D013186:Farnesyl-Diphosphate Farnesyltransferase