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Antimicrobial Agents and Chemotherapy, November 2002, p. 3343-3347, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3343-3347.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Defining and Combating the Mechanisms of Triclosan Resistance in Clinical Isolates of Staphylococcus aureus

Frank Fan,1 Kang Yan,1 Nicola G. Wallis,1,{dagger} Shannon Reed,1 Terrance D. Moore,1 Stephen F. Rittenhouse,1 Walter E. DeWolf Jr.,1 Jianzhong Huang,1 Damien McDevitt,1 William H. Miller,1 Mark A. Seefeld,1 Kenneth A. Newlander,1 Dalia R. Jakas,1 Martha S. Head,2 and David J. Payne1*

Microbial, Musculoskeletal and Proliferative Diseases CEDD,1 Computational and Structural Sciences, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 194262

Received 9 May 2002/ Returned for modification 20 June 2002/ Accepted 26 July 2002

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.

* Corresponding author. Mailing address: Microbial, Musculoskeletal and Proliferative Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Rd., Collegeville, PA 19426-0989. Phone: (610) 917-7355. Fax: (610) 917-7901. E-mail: david_j_payne{at}gsk.com.

{dagger} Present address: Astex-Technology, Cambridge CB4 0WE, United Kingdom.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3343-3347, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3343-3347.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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