title: Defining and combating the mechanisms of triclosan resistance in clinical isolates of Staphylococcus aureus.
abstract: The MICs of triclosan for 31 clinical isolates of Staphylococcus aureus were 0.016 micro g/ml (24 strains), 1 to 2 micro g/ml (6 strains), and 0.25 micro g/ml (1 strain). All the strains for which triclosan MICs were elevated (>0.016 micro g/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 micro g/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 micro g/ml for these strains. Three novel, potent inhibitors of FabI (50% inhibitory concentrations, < or =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.
authors.affiliation: Microbial, Musculoskeletal and Proliferative Diseases CEDD. Computational and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Fan
authors.forename: Kang
authors.initials: K
authors.lastname: Yan
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
authors.forename: Shannon
authors.initials: S
authors.lastname: Reed
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Moore
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Rittenhouse
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Damien
authors.initials: D
authors.lastname: McDevitt
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seefeld
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newlander
authors.forename: Dalia R
authors.initials: DR
authors.lastname: Jakas
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: David J
authors.initials: DJ
authors.lastname: Payne
mesh_terms: D000891:Anti-Infective Agents, Local / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification; D011485:Protein Binding; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D014260:Triclosan / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000891:Anti-Infective Agents, Local; D014260:Triclosan; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)