Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results
- 20 May 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 52 (13), 3869-3880
- https://doi.org/10.1021/jm9001764
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 Ki 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 (IC50 = 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.Keywords
This publication has 25 references indexed in Scilit:
- Phosphonosulfonates Are Potent, Selective Inhibitors of Dehydrosqualene Synthase and Staphyloxanthin Biosynthesis in Staphylococcus aureusJournal of Medicinal Chemistry, 2009
- Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme DataJournal of Medicinal Chemistry, 2008
- “Superbugs Bunny” Outsmarts Our Immune DefenseChemMedChem, 2008
- Inhibitors of Sterol Biosynthesis as Staphylococcus aureus AntibioticsAngewandte Chemie-International Edition, 2008
- A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus VirulenceScience, 2008
- Staphyloxanthin Plays a Role in the Fitness of Staphylococcus aureus and Its Ability To Cope with Oxidative StressInfection and Immunity, 2006
- XtalView/Xfit—A Versatile Program for Manipulating Atomic Coordinates and Electron DensityJournal of Structural Biology, 1999
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- LIGPLOT: a program to generate schematic diagrams of protein-ligand interactionsProtein Engineering, Design and Selection, 1995
- PROCHECK: a program to check the stereochemical quality of protein structuresJournal of Applied Crystallography, 1993