Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: Restricted array of mutations associated with drug resistance

The catalase-peroxidase gene (katG) and a two-gene locus (inhA) containing mutations associated with resistance to isoniazid in Mycobacterium tuberculosis were sequenced in 34 resistant and 12 susceptible strains. Virtually all resistant organisms had amino acid changes in KatG or nucleotide substitutions upstream of inhA. A region of katG encoding two amino acids frequently altered in resistant strains (residues Ser315 and Arg463) and the inhA locus were sequenced in 10 susceptible and 51 isoniazid-resistant isolates from the Netherlands. Most (84%) of the resistant isolates had mutations in katG or the inhA locus or lacked katG. Together, ∼75% of isoniazid-resistant isolates had replacements at amino acids 315 or 463 in KatG or nucleotide substitutions upstream of inhA. All 16 strains of Mycobacterium bovis and Mycobacterium microti studied had Leu463 rather than Arg463 in KatG, an observation consistent with the hypothesis that Leu463 is the ancestral condition in M. tuberculosis.