MECHANISM OF ACTION OF DIAZABORINES

The diazaborine family of compounds have antibacterial properties agai nst a range of Gram-negative bacteria. Initially, this was thought to be due to the prevention of lipopolysaccharide synthesis. More recentl y, the molecular target of diazaborines has been identified as the NAD (P)H-dependent enoyl acyl carrier protein reductase (ENR), which catal yses the last reductive step of fatty acid synthase. ENR from Mycobact erium tr tuberculosis is the target for the front-line antituberculosi s drug isoniazid. The emergence of isoniazid resistance strains of M, tuberculosis, a chronic infectious disease that already kills more peo ple than any other infection, is currently causing great concern over the prospects for its future treatment, and it has reawakened interest in the mechanism of diazaborine action. Diazaborines only inhibit ENR in the presence of the nucleotide cofactor, and this has been explain ed through the analysis of the x-ray crystallographic structures of a number of Escherichia coli ENR-NAD(+)-diazaborine complexes that showe d the formation of a covalent bond between the boron atom in the diaza borines and the 2'-hydroxyl of the nicotinamide ribose moiety that gen erates a noncovalently bound bisubstrate analogue. The similarities in catalytic chemistry and in the conformation of the nucleotide cofacto r across the wider family of NAD(P)-dependent oxidoreductases suggest that there are generic opportunities to mimic the interactions seen he re in the rational design of bisubstrate analogue inhibitors for other NAD(P)H-dependent oxidoreductases. (C) 1998 Elsevier Science Inc.