Structural basis and mechanism of enoyl reductase inhibition by triclosan

The enoyl-acyl carrier protein reductase (ENR) is involved in bacterial fat ty acid biosynthesis and is the target of the antibacterial diazaborine com pounds and the front-line antituberculosis drug isoniazid. Recent studies s uggest that ENR is also the target for the broad-spectrum biocide triclosan . The 1.75 Angstrom crystal structure of EnvM, the ENR from Escherichia col i, in complex with triclosan and NADH reveals that triclosan binds specific ally to EnvM. These data provide a molecular mechanism for the antibacteria l activity of triclosan and substantiate the hypothesis that its activity r esults from inhibition of a specific cellular target rather than non-specif ic disruption of the bacterial cell membrane. This has important implicatio ns for the emergence of drug-resistant bacteria, since triclosan is an addi tive in many personal care products such as toothpastes, mouthwashes and so aps. Based on this structure, rational design of triclosan derivatives is p ossible which might be effective against recently identified triclosan-resi stant bacterial strains. (C) 1999 Academic Press.