Chemical Genetic Approaches to Understanding Mycobacterial Pathogenesis
During Mycobacterium tuberculosis (Mtb) infection, host-derived stresses induce physiological changes in the bacteria that lead to the formation of antibiotic-tolerant persisters. The recalcitrance of persister Mtb to therapy precludes eradication of the infection and contributes to the formation of antibiotic resistant bacteria by requiring long durations of treatment. Using a chemical approach to dissect hypoxia-induced persister formation, we identified small molecules that inhibit the development of isoniazid (INH) tolerant Mtb. INH is a key component of anti-tuberculosis therapy and the rise in INH-resistance is crippling efforts to control the tuberculosis epidemic. Mechanistic studies revealed that these small molecule mycobacteria tolerance inhibitors (MTIs) dysregulate redox homeostasis and electron transport, thus implicating these processes in drug and stress tolerance. In addition, MTIs prevent the selection for INH-resistant mutants and restore INH-sensitivity in a katG mutant that is otherwise resistant to INH, which has never before been reported as possible. Thus, MTIs represent a novel strategy to reverse INH resistance and provide new insight into mechanisms of antibiotic tolerance.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.