Journal article
Phosphonosulfonates Are Potent, Selective Inhibitors of Dehydrosqualene Synthase and Staphyloxanthin Biosynthesis in Staphylococcus aureus
Journal of medicinal chemistry, Vol.52(4), pp.976-988
2009
DOI: 10.1021/jm801023u
PMCID: PMC2765255
PMID: 19191557
Abstract
Staphylococcus aureus produces a golden carotenoid virulence factor called staphyloxanthin (STX), and we report here the inhibition of the enzyme, dehydrosqualene synthase (CrtM), responsible for the first committed step in STX biosynthesis. The most active compounds are halogen-substituted phosphonosulfonates, with Ki values as low as 5 nM against the enzyme and IC50 values for STX inhibition in S. aureus as low as 11 nM. There is, however, only a poor correlation (R2 = 0.27) between enzyme and cell pIC50 (= −log10 IC50) values. The ability to predict cell from enzyme data improves considerably (to R2 = 0.72) with addition of two more descriptors. We also investigated the activity of these compounds against human squalene synthase (SQS), as a counterscreen, finding several potent STX biosynthesis inhibitors with essentially no squalene synthase activity. These results open up the way to developing potent and selective inhibitors of an important virulence factor in S. aureus, a major human pathogen.
Details
- Title: Subtitle
- Phosphonosulfonates Are Potent, Selective Inhibitors of Dehydrosqualene Synthase and Staphyloxanthin Biosynthesis in Staphylococcus aureus
- Creators
- YONGCHENG SONG - Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United StatesFu-Yang LIN - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesVictor NIZET - Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0687, United StatesEric OLDFIELD - Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United StatesFENGLIN YIN - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesMary HENSLER - Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0687, United StatesCarlos A RODRIGUES POVEDA - Instituto de Parasitologd y Biomedicina López-Neyra, Consejo Superior de Investigaciones Cienti ficas, Granada, SpainDushyant MUKKAMALA - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesRONG CAO - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesHONG WANG - Division of Rheumatology, Department of Internal Medicine, EMRB 400F, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, United StatesCraig T MORITA - Division of Rheumatology, Department of Internal Medicine, EMRB 400F, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, United StatesDolores GONZALEZ PACANOWSKA - Instituto de Parasitologd y Biomedicina López-Neyra, Consejo Superior de Investigaciones Cienti ficas, Granada, Spain
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.52(4), pp.976-988
- DOI
- 10.1021/jm801023u
- PMID
- 19191557
- PMCID
- PMC2765255
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- American Chemical Society
- Language
- English
- Date published
- 2009
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984094632302771
Metrics
19 Record Views