Defining and Combating the Mechanisms of Triclosan Resistance in Clinical Isolates of Staphylococcus aureus
by
Frank Fan, Kang Yan, Nicola G. Wallis,
Shannon Reed, Terrance D. Moore, Stephen F. Rittenhouse,
Walter E. DeWolf, Jr., Jianzhong Huang, Damien McDevitt,
William H. Miller, Mark A. Seefeld, Kenneth A. Newlander,
Dalia R. Jakas, Martha S. Head, and David J. Payne.
Microbial, Musculoskeletal and Proliferative Diseases CEDD,
Computational and Structural Sciences,
GlaxoSmithKline Pharmaceuticals,
Collegeville, Pennsylvania 19426. Antimicrob Agents Chemother. 2002 November; 46(11): 3343–3347.
ABSTRACT
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.