Phenotypic Drug Tolerance in Mycobacterium tuberculosis : How to kill persisters
Hartman, Travis E.
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The achievement of the WHO's "Stop TB" program has been largely overlooked, but mortality and incidence rates for clinically diagnosed tuberculosis have fallen for the second straight year. Although the estimated 1.4 million deaths attributed to the disease are still unacceptably high for a curable disease, the success of Stop TB can be partially ascribed to the DOTS program which closely monitors patient adherence to chemotherapy. Patient compliance may be improved by cutting the duration of antibiotic treatment to a more manageable course.;The recommended chemotherapy for treatment of susceptible pulmonary tuberculosis entails a two month, four-drug course followed by a four month continuation phase with the purpose of targeting bacteria which were initially unresponsive. If followed in its entirety, this program can effectively "cure" tuberculosis. The necessity for such a protracted regimen is due to the presence of persister cells which are insensitive to antibiotic treatment and only succumb to drug pressure at a reduced rate. In no other organism does the presence of this persister population beget more dire consequences than in Mycobacterium tuberculosis infection.;We report that kinetics of multidrug killing of M. tuberculosis by the two front-line antibiotics which make up the continuation phase (INH and RIF) can be improved in a strain that harbors a deletion in one of two annotated succinate dehydrogenase operons (sdh1). We show mechanistically that the enhanced killing of the sdh1 mutant is due to a loss of respiratory control resulting in increased respiratory flux, a hyperpolarized membrane, and an increased proportion of reduced electron carrier (menaquinol) in the membrane. This work shows that Sdh1 is the governor of cellular respiration in M. tuberculosis and we propose a new concept by which tuberculosis chemotherapy with current frontline drugs could be shortened by enhancing cellular respiration.;The effect of increasing respiratory flux in a condition in which the organism is unprepared to deal with that flux is the generation of reactive oxygen species. We demonstrate that reactive oxygen species are not a general mechanism of bactericidal activity for antitubercual drugs. They can, however, be induced under certain conditions to affect killing, thus presenting an attractive avenue for new drug design.