MOLECULAR CHARACTERIZATION OF DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS

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Because of the emergence of multiply drug resistant Mycobacterium tuberculosis strains in clinical isolates, our laboratory has begun a molecular characterization of drug resistance in M. tuberculosis. Resistance to isoniazid (INH), the primary drug for treatment of tuberculosis, is frequently correlated with a loss of catalase-peroxidase activity. Recently, we have demonstrated by using peroxidase assays and an affinity purified polyclonal antibody that an INH resistant mutant of the catalase-peroxidase positive M. tuberculosis H37Rv strain has no detectable catalase protein. Furthermore, Southern blot hybridizations with a catalase-peroxidase gene probe have demonstrated that the gene encoding this protein is deleted from the INH resistant strain. We are currently examining other INH resistant strains to elucidate the role of catalase in INH resistance. In prokayotes and eukaryotes, resistance to streptomyocin (SM), another primary tuberculosis drug, often results from mutations in the ribosomal S12 protein gene. We have recently demonstrated with PCR and nucleotide sequence analyses that 2 different SM resistant M. tuberculosis strains have identical mutations in the S12 protein gene. The location of these mutations within the M. tuberculosis S12 gene is identical to the site of S12 mutations previously described in other SM resistant cells.