Mechanism of Triclosan Inhibition of Bacterial Fatty Acid Synthesis

• Published in: The Journal of biological chemistry Vol. 274; no. 16; pp. 11110 - 11114
• Main Authors: Heath, R J, Rubin, J R, Holland, D R, Zhang, E, Snow, M E, Rock, C O
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 16.04.1999
• Subjects: Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Escherichia coli; 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.16.11110

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.