CHARACTERIZATION OF THE CATALASE-PEROXIDASE GENE (KATG) AND INHA LOCUS IN ISONIAZID-RESISTANT AND ISONIAZID-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) contai ning mutations associated with resistance to isoniazid in Mycobacteriu m tuberculosis were sequenced in 34 resistant and 12 susceptible strai ns. Virtually all resistant organisms had amino acid changes in KatG o r nucleotide substitutions upstream of inhA, A region of katG encoding two amino acids frequently altered in resistant strains (residues Ser 315 and Arg463) and the inhA locus were sequenced in 10 susceptible an d 51 isoniazid-resistant isolates from the Netherlands, Most (84%) of the resistant isolates had mutations in katG or the inhA locus or lack ed katG, Together, similar to 75% of isoniazid-resistant isolates had replacements at amino acids 315 or 463 in KatG or nucleotide substitut ions upstream of inhA. All 16 strains of Mycobacterium bovis and Mycob acterium microti studied had Leu463 rather than Arg463 in KatG, an obs ervation consistent with the hypothesis that Leu463 is the ancestral c ondition in M. tuberculosis.