PMID:10196195
| Citation |
Heath, RJ, Rubin, JR, Holland, DR, Zhang, E, Snow, ME and Rock, CO (1999) Mechanism of triclosan inhibition of bacterial fatty acid synthesis. J. Biol. Chem. 274:11110-4 |
|---|---|
| Abstract |
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. |
| Links | |
| Keywords |
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Fatty Acids/antagonists & inhibitors; Fatty Acids/biosynthesis; Models, Molecular; Molecular Structure; Mutation, Missense; NAD/metabolism; Oxidoreductases/antagonists & inhibitors; Oxidoreductases/genetics; Oxidoreductases/metabolism; Protein Binding; Triclosan/chemistry; Triclosan/metabolism; Triclosan/pharmacology |
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