ANALYSIS OF THE OXYR-AHPC REGION IN ISONIAZID-RESISTANT AND ISONIAZID-SUSCEPTIBLE MYCOBACTERIUM-TUBERCULOSIS COMPLEX ORGANISMS RECOVERED FROM DISEASED HUMANS AND ANIMALS IN DIVERSE LOCALITIES

Automated DNA sequencing was used to analyze the oxyR-ahpC region in 2 29 Mycobacterium tuberculosis complex isolates recently recovered from diseased humans and animals, The entire 1,221-bp region was studied i n 118 isolates, and 111 other isolates were sequenced for oxyR, ahpC, or the 105-bp oxyR-ahpC intergenic region, The sample included isoniaz id (INH)-susceptible and -resistant organisms in which the katG gene a nd inhA locus had previously been sequenced in their entirety to ident ify polymorphisms, A total of 16 polymorphic sites was identified, inc luding 5 located in oxyR, 2 in ahpC, and 9 in the 105-bp intergenic re gion, All polymorphic sites located in the intergenic region, and the two missense substitutions identified in ahpC, occurred in INH-resista nt organisms, In contrast, there was no preferential association of po lymorphisms in oxyR, a pseudogene, with INH-resistant organisms, Surpr isingly, most INH-resistant strains with KatG codon 315 substitutions that substantially reduce catalase-peroxidase activity and confer high MICs of INH lacked alterations in the ahpC gene or oxyR-ahpC interven ing region, Taken together, the data are consistent with the hypothesi s that some polymorphisms located in the ahpC-oxyR intergenic region a re selected for after reduction in catalase or peroxidase activity att ributable to katG alterations arising with INH therapy, These mutation s are uncommon in recently recovered clinically significant organisms, and hence, there is no strict association with INH-resistant patient isolates, The ahpC compensatory mutations are apparently uncommon beca use strains with a KatG null phenotype are relatively rare among epide miologically independent INH-resistant organisms.