ABSTRACT
Introduction ........................................................................................................ 314 Development of Tuberculosis Chemotherapy .................................................... 314 Drug-Resistant Tuberculosis .............................................................................. 315
Defi nition ................................................................................................ 315 Epidemiology .......................................................................................... 315
Molecular Basis of Drug Resistance .................................................................. 316 Aminoglycosides .................................................................................... 316
Streptomycin ................................................................................ 316 Other Aminoglycosides ............................................................... 318
Rifamycins .............................................................................................. 319 Development of Rifamycins ........................................................ 319 Rifampin ...................................................................................... 319
Isoniazid .................................................................................................. 320 Historical Studies ......................................................................... 320 Drug Activation ........................................................................... 320 Drug Targets ................................................................................ 321 Other INH Resistance Mechanisms ............................................ 323 Compensatory Mutations ............................................................. 324
Pyrazinamide .......................................................................................... 324 Ethambutol .............................................................................................. 327 Fluoroquinolones .................................................................................... 328 New Drugs .............................................................................................. 329
Conclusions ........................................................................................................ 330 Acknowledgments .............................................................................................. 330 References .......................................................................................................... 330
Tuberculosis is the leading cause of death from a curable infectious disease and there were an estimated 8.9 million new cases of tuberculosis in 2004 [1]. Tackling the global burden of tuberculosis is a major public health challenge that has become more daunting with the realization that strains of multiply drug-resistant Mycobacterium tuberculosis (MDR-TB) are increasing rapidly. Between 2000 and 2004, global estimates of MDR-TB incidence increased from 270,000 to over 400,000 new cases annually [2]. These strains are diffi cult to cure because they usually require two years of therapy with costly and poorly tolerated regimens usually comprising a minimum of fi ve drugs. The ultimate control of MDR-TB will require multiple interventions, but a complete understanding of the mechanisms of drug resistance in M. tuberculosis is essential for devising rapid diagnostics and developing new drugs. In this chapter, we review what is currently known about the genetics of resistance to the most important antimycobacterial drugs.
