CHARACTERIZATION OF RIFAMPIN RESISTANCE IN PATHOGENIC MYCOBACTERIA

The emergence of rifampin-resistant strains of pathogenic mycobacteria has threatened the usefulness of this drug in treating mycobacterial diseases. Critical to the treatment of individuals infected with resis tant strains is the rapid identification of these strains directly fro m clinical specimens. It has been shown that resistance to rifampin in Mycobacterium tuberculosis and Mycobacterium leprae apparently involv es mutations in the rpoB gene encoding the beta-subunit of the RNA pol ymerases of these species. DNA sequences were obtained from a 305-bp f ragment of the rpoB gene from 110 rifampin-resistant and 10 rifampin-s usceptible strains of M. tuberculosis from diverse geographical region s throughout the world. In 102 of 110 rifampin-resistant strains 16 mu tations affecting 13 amino acids were observed. No mutations were obse rved in rifampin-susceptible strains. No association was found between particular mutations in the rpoB gene and drug susceptibility pattern s of multidrug-resistant M. tuberculosis strains. Drug-resistant M. tu berculosis strains from the same outbreak and exhibiting the same IS61 10 DNA fingerprint and drug susceptibility pattern contained the same mutation in the rpoB gene. However, mutations are not correlated with IS6110 profiling outside of epidemics. The evolution of rifampin resis tance as a consequence of mutations in the rpoB gene was documented in a patient who developed rifampin resistance during the course of trea tment. Rifampin-resistant strains of M. leprae, Mycobacterium avium, a nd Mycobacterium africanum contained mutations in the rpoB gene simila r to that documented for M. tuberculosis. This information served as t he basis for developing a rapid DNA diagnostic assay (PCR-heteroduplex formation) for the detection of rifampin susceptibility of M. tubercu losis.