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J Biol Chem, Vol. 274, Issue 16, 11110-11114, April 16, 1999
,¶
From the Triclosan is a broad-spectrum antibacterial agent
that inhibits bacterial fatty acid synthesis at the enoyl-acyl carrier
protein reductase (FabI) step. Resistance to triclosan in
Escherichia coli is acquired through a missense mutation in
the fabI gene that leads to the expression of FabI[G93V].
The specific activity and substrate affinities of FabI[G93V] are
similar to FabI. Two different binding assays establish that triclosan
dramatically increases the affinity of FabI for NAD+. In
contrast, triclosan does not increase the binding of NAD+
to FabI[G93V]. The x-ray crystal structure of the
FabI-NAD+-triclosan complex confirms that hydrogen bonds
and hydrophobic interactions between triclosan and both the protein and
the NAD+ cofactor contribute to the formation of a stable
ternary complex, with the drug binding at the enoyl substrate site.
These data show that the formation of a noncovalent "bi-substrate"
complex accounts for the effectiveness of triclosan as a FabI inhibitor and illustrates that mutations in the FabI active site that interfere with the formation of a stable FabI-NAD+-triclosan ternary
complex acquire resistance to the drug.
Department of Biochemistry, St. Jude
Children's Research Hospital, Memphis, Tennessee 38105, the
§ Department of Biomolecular Structure and Drug Design,
Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105, and
the ¶ Department of Biochemistry, University of Tennessee,
Memphis, Tennessee 38163
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