Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results.
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.
Song
Yongcheng
Y
Department of Chemistry and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Liu
Chia-I
CI
Lin
Fu-Yang
FY
No
Joo Hwan
JH
Hensler
Mary
M
Liu
Yi-Liang
YL
Jeng
Wen-Yih
WY
Low
Jennifer
J
Liu
George Y
GY
Nizet
Victor
V
Wang
Andrew H-J
AH
Oldfield
Eric
E
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
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