Document Detail

Mechanism of triclosan inhibition of bacterial fatty acid synthesis.
MedLine Citation:
PMID:  10196195     Owner:  NLM     Status:  MEDLINE    
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.
R J Heath; J R Rubin; D R Holland; E Zhang; M E Snow; C O Rock
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-05-17     Completed Date:  1999-05-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  11110-4     Citation Subset:  IM    
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Fatty Acids / antagonists & inhibitors*,  biosynthesis
Models, Molecular
Molecular Structure
Mutation, Missense
NAD / metabolism
Oxidoreductases / antagonists & inhibitors*,  genetics,  metabolism
Protein Binding
Triclosan / chemistry,  metabolism,  pharmacology*
Grant Support
Reg. No./Substance:
0/Fatty Acids; 3380-34-5/Triclosan; 53-84-9/NAD; EC 1.-/Oxidoreductases; EC Reductase (NADH)

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