Defining and Combating the Mechanisms of Triclosan Resistance in Clinical Isolates of Staphylococcus aureus
| Autor: | William H. Miller, Frank Fan, Nicola G. Wallis, Mark A. Seefeld, Walter E. DeWolf, Martha S. Head, David J. Payne, Damien McDevitt, Jianzhong Huang, Terrance D. Moore, Dalia R. Jakas, Kenneth A. Newlander, Kang Yan, Stephen Rittenhouse, Shannon L. Reed |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Staphylococcus aureus Micrococcaceae Blotting Western Molecular Conformation Microbial Sensitivity Tests Crystallography X-Ray Staphylococcal infections medicine.disease_cause Microbiology chemistry.chemical_compound Minimum inhibitory concentration Mechanisms of Resistance Drug Resistance Bacterial medicine Humans Pharmacology (medical) Antibacterial agent Pharmacology chemistry.chemical_classification biology Staphylococcal Infections biology.organism_classification medicine.disease Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) Triclosan Kinetics Infectious Diseases Enzyme chemistry Enzyme inhibitor Anti-Infective Agents Local biology.protein Oxidoreductases Protein Binding |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 46:3343-3347 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.46.11.3343-3347.2002 |
| Popis: | The MICs of triclosan for 31 clinical isolates of Staphylococcus aureus were 0.016 μg/ml (24 strains), 1 to 2 μg/ml (6 strains), and 0.25 μg/ml (1 strain). All the strains for which triclosan MICs were elevated (>0.016 μg/ml) showed three- to fivefold increases in their levels of enoyl-acyl carrier protein (ACP) reductase (FabI) production. Furthermore, strains for which triclosan MICs were 1 to 2 μg/ml overexpressed FabI with an F204C alteration. Binding studies with radiolabeled NAD + demonstrated that this change prevents the formation of the stable triclosan-NAD + -FabI complex, and both this alteration and its overexpression contributed to achieving MICs of 1 to 2 μg/ml for these strains. Three novel, potent inhibitors of FabI (50% inhibitory concentrations, ≤64 nM) demonstrated up to 1,000-fold better activity than triclosan against the strains for which triclosan MICs were elevated. None of the compounds tested from this series formed a stable complex with NAD + -FabI. Consequently, although the overexpression of wild-type FabI gave rise to an increase in the MICs, as expected, overexpression of FabI with an F204C alteration did not cause an additional increase in resistance. Therefore, this work identifies the mechanisms of triclosan resistance in S. aureus , and we present three compounds from a novel chemical series of FabI inhibitors which have excellent activities against both triclosan-resistant and -sensitive clinical isolates of S. aureus . |
| Databáze: | OpenAIRE |
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