Chapter 17. Recent Advances in the Chemistry and Biology of Anti-mycobacterial Agents

Publisher Summary New knowledge is needed in the areas of in vitro and in vivo drug susceptibility assay methods, mycobacterial molecular biology, and anti-mycobacterial drug mechanism of action and drug discovery. This chapter discusses the anti-mycobacterial agents with focus on the multidrug-resistant (MDR) tuberculosis. There is an urgent need for new research approaches to help combat the spread of tuberculosis and other mycobacterial infections, including M. avium and M. leprae . With the exception of rifampin, little is known about the mechanisms of action for the drugs used to treat tuberculosis. The principal anti-tubercular drug, isonicotinic acid hydrazide (INH), is well specific for mycobacteria of the tuberculosis complex. The rifamycins and semi-synthetic rifamycins belong to a novel class of macrolide antibiotics that feature a propionate-derived chain bridging a tricyclic napthalene core. The rifamycins are active in vitro against gram-positive bacteria, including M. tuberculosis and, to a lesser extent, gram-negative bacteria. A modified rifampicin derivative has been synthesized and evaluated for anti-mycobacterial activity. Like KRM-1648, this derivative is more potent in vitro against rifampicin susceptible strains of M. tuberculosis and M. avium complex than rifampicin. Beside these agents, classical macrolides have found no particular place in the anti-tubercular chemotherapy. On the other hand, the ability of certain members of this class to concentrate in tissues of the respiratory tract as well as macrophages, neutrophils, and T-lymphocytes has led to the clinical use of newer macrolides (azithromycin, clarithromycin) against opportunistic mycobacteria, such as M. aviurn complex (MAC). These newer agents are superior to classic macrolides in producing higher oral blood levels and in causing less gastro intestinal (GI) upset.