Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update.

Knowledge of the molecular genetic basis of resistance to antituberculous agents has advanced rapidly since we reviewed this topic 3 years ago. Virtually all isolates resistant to rifampin and related rifamycins have a mutation that alters the sequence of a 27-amino-acid region of the beta subunit of ribonucleic acid (RNA) polymerase. Resistance to isoniazid (INH) is more complex. Many resistant organisms have mutations in the katG gene encoding catalase-peroxidase that result in altered enzyme structure. These structural changes apparently result in decreased conversion of INH to a biologically active form. Some INH-resistant organisms also have mutations in the inhA locus or a recently characterized gene (kasA) encoding a beta-ketoacyl-acyl carrier protein synthase. Streptomycin resistance is due mainly to mutations in the 16S rRNA gene or the rpsL gene encoding ribosomal protein S12. Resistance to pyrazinamide in the great majority of organisms is caused by mutations in the gene (pncA) encoding pyrazinamidase that result in diminished enzyme activity. Ethambutol resistance in approximately 60% of organisms is due to amino acid replacements at position 306 of an arabinosyltransferase encoded by the embB gene. Amino acid changes in the A subunit of deoxyribonucleic acid gyrase cause fluoroquinolone resistance in most organisms. Kanamycin resistance is due to nucleotide substitutions in the rrs gene encoding 16S rRNA. Multidrug resistant strains arise by sequential accumulation of resistance mutations for individual drugs. Limited evidence exists indicating that some drug resistant strains with mutations that severely alter catalase-peroxidase activity are less virulent in animal models. A diverse array of strategies is available to assist in rapid detection of drug resistance-associated gene mutations. Although remarkable advances have been made, much remains to be learned about the molecular genetic basis of drug resistance in Mycobacterium tuberculosis. It is reasonable to believe that development of new therapeutics based on knowledge obtained from the study of the molecular mechanisms of resistance will occur.