Evolution of drug resistance in Mycobacterium tuberculosis: Clinical and molecular perspective

Drug-resistant tuberculosis poses a significant threat to human health, and it is important to understand how the resistance emerges if we are to reverse the upward trend. Treatment with internationally approved regimens results in a very high cure rate with few relapses and without the emergence of resistance. These regimens are effective in preventing the emergence of resistance because combination chemotherapy makes it highly unlikely that there will be a spontaneous mutant resistant to all of the components of chemotherapy. Patients with uncomplicated tuberculosis who receive inadequate treatment provide a selection advantage for resistant mutants because bacteria may be exposed to monotherapy, permitting the emergence of resistance to single agents and then to multiple agents as the protection of combination chemotherapy is eroded. That M. tuberculosis cells within the body are susceptible to different components of antituberculosis chemotherapy means that the risk of resistant mutants emerging is higher than would be expected if the whole population of bacterial cells could be counted together. Clinical complications such as empyema and extensive cavitation permit a large population to develop in a compartment into which drugs may not penetrate. This large bacterial pool increases the population for mutation, and with poor penetration there is an increased likelihood of resistance emerging. A similar situation may develop in patients with extensive disease or poor immunity (Fig. 1). We have learned that some physiological conditions may induce a hypermutable state, making multiple resistance more likely. The assumption that resistant organisms are less fit than wild-type strains may not be correct, as the initial fitness deficits may be attenuated by adaptation by multiple passage. Instances of isoniazid resistance, where attenuated virulence is common, may occur because the molecular mechanism of resistance directly affects a system required by the organism for intracellular survival. The important lesson these clinical and molecular studies teach us is that resistant organisms over time will be fully virulent and that if we are to prevent an epidemic of multiple-drug-resistant tuberculosis we must take steps to ensure that all patients are diagnosed and effectively treated so that resistant strains are not created and transmitted in the community.