Mechanisms of Action and Resistance of the Antimycobacterial Agents

This chapter will review the mechanisms of action and resistance of the antimycobacterial agents, with an emphasis on the four first-line antituberculosis drugs isoniazid, rifampin, pyrazinamide, and ethambutol. The mechanisms of action of other drugs used to treat mycobacterial infections, including the fluoroquinolones, aminoglycosides, and the macrolides, will be reviewed elsewhere in this book and this chapter will focus on specific mutations associated with resistance to these agents in M. tuberculosis and M. avium complex. This chapter includes mechanistic studies carried out in M. smegmatis, which, because of its relatedness to M. tuberculosis, its fast-growing nature and lack of pathogenicity, and its relative genetic tractability, is widely used as a model system to study mycobacterial physiology. The phenomenon of M. tuberculosis phenotypic drug tolerance will not be addressed in this section, and discussion will be limited to genotypic mechanisms of drug resistance.