MISSENSE MUTATIONS IN THE CATALASE-PEROXIDASE GENE, KATG, ARE ASSOCIATED WITH ISONIAZID RESISTANCE IN MYCOBACTERIUM-TUBERCULOSIS

The toxicity of the powerful anti-tuberculosis drug isoniazid (INH) is believed to be mediated by the haem-containing enzyme catalase-peroxi dase, encoded by the katG gene of Mycobacterium tuberculosis. Compelli ng evidence for this was obtained by studying a panel of INH-resistant clinical isolates using a novel strategy based on the polymerase chai n reaction and single-strand-conformation polymorphism analysis (PCR-S SCP) to detect mutations in katG. In most cases INH resistance was ass ociated with missense mutations while in a small number of strains the gene had been completely, or partially, deleted. The missense mutatio ns fell into two groups, the larger of which contained several indepen dent mutations that affected the N-terminal peroxidase domain of the p rotein, resulting in the production of a catalase peroxidase with stro ngly reduced enzyme activity and increased heat lability. The effects of these substitutions could be interpreted by means of molecular mode lling using the crystal structure of the related enzyme cytochrome c p eroxidase from yeast as a template. The second group comprises a frequ ently occurring amino acid substitution and a single mutation that are both located in the C-terminal domain but do not noticeably alter eit her enzyme activity or heat stability.