Mechanism of action of diazaborines.
The diazaborine family of compounds have antibacterial properties against a range of gram-negative bacteria. Initially, this was thought to be due to the prevention of lipopolysaccharide synthesis. More recently, the molecular target of diazaborines has been identified as the NAD(P)H-dependent enoyl acyl carrier protein reductase (ENR), which catalyses the last reductive step of fatty acid synthase. ENR from Mycobacterium tuberculosis is the target for the front-line antituberculosis drug isoniazid. The emergence of isoniazid resistance strains of M. tuberculosis, a chronic infectious disease that already kills more people 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 explained through the analysis of the x-ray crystallographic structures of a number of Escherichia coli ENR-NAD+-diazaborine complexes that showed the formation of a covalent bond between the boron atom in the diazaborines and the 2'-hydroxyl of the nicotinamide ribose moiety that generates a noncovalently bound bisubstrate analogue. The similarities in catalytic chemistry and in the conformation of the nucleotide cofactor across the wider family of NAD(P)-dependent oxidoreductases suggest that there are generic opportunities to mimic the interactions seen here in the rational design of bisubstrate analogue inhibitors for other NAD(P)H-dependent oxidoreductases.
Baldock
C
C
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, The University of Sheffield, UK.
de Boer
G J
GJ
Rafferty
J B
JB
Stuitje
A R
AR
Rice
D W
DW
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D006571:Heterocyclic Compounds