CRYSTAL-STRUCTURE AND FUNCTION OF THE ISONIAZID TARGET OF MYCOBACTERIUM-TUBERCULOSIS

Resistance to isoniazid in Mycobacterium tuberculosis can be mediated by substitution of alanine for serine 94 in the InhA protein, the drug 's primary target. InhA was shown to catalyze the beta-nicotinamide ad enine dinucleotide (NADH)-specific reduction of 2-trans-enoyl-acyl car rier protein, an essential step in fatty acid elongation. Kinetic anal yses suggested that isoniazid resistance is due to a decreased affinit y of the mutant protein for NADH. The three-dimensional structures of wild-type and mutant InhA, refined to 2.2 and 2.7 angstroms, respectiv ely, revealed that drug resistance is directly related to a perturbati on in the hydrogen-bonding network that stabilizes NADH binding.