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J Biol Chem, Vol. 275, Issue 7, 4654-4659, February 18, 2000
From the Enoyl-acyl carrier protein reductase (FabI) plays
a determinant role in completing cycles of elongation in type II fatty
acid synthase systems and is an important target for antibacterial drugs. The FabI component of Staphylococcus aureus (saFabI)
was identified, and its properties were compared with Escherichia coli FabI (ecFabI). ecFabI and saFabI had similar specific
activities, and saFabI expression complemented the E. coli
fabI(Ts) mutant, illustrating that the Gram-positive FabI was
interchangeable with the Gram-negative FabI enzyme. However, ecFabI was
specific for NADH, whereas saFabI exhibited specific and positive
cooperative binding of NADPH. Triclosan and hexachlorophene inhibited
both ecFabI and saFabI. The triclosan-resistant ecFabI(G93V) protein was also refractory to hexachlorophene inhibition, illustrating that
both drugs bind at the FabI active site. Both the introduction of a
plasmid expressing the safabI gene or a missense mutation in the chromosomal safabI gene led to triclosan resistance
in S. aureus; however, these strains did not exhibit
cross-resistance to hexachlorophene. The replacement of the ether
linkage in triclosan by a carbon bridge in hexachlorophene prevented
the formation of a stable FabI-NAD(P)+-drug ternary
complex. Thus, the formation of this ternary complex is a key
determinant of the antibacterial activity of FabI inhibitors.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF197058 (fabI gene from S. aureus strain RN4220).
Inhibition of the Staphylococcus aureus
NADPH-dependent Enoyl-Acyl Carrier Protein Reductase by
Triclosan and Hexachlorophene*
,¶
Department of Biochemistry, St. Jude
Children's Research Hospital, Memphis, Tennessee 38105, the
§ Department of Infectious Diseases, Parke-Davis
Pharmaceutical Research, Ann Arbor, Michigan 48105, and the
¶ Department of Biochemistry, University of Tennessee,
Memphis, Tennessee 38163
*
This work was supported by National Institutes of Health
Grants GM 34496, Cancer Center (CORE) Support Grant CA 21765, and the
American Lebanese Syrian Associated Charities.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Tel.: 901-495-3491; Fax:
901-525-8025; E-mail: charles.rock@stjude.org.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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