| A major roadblock in the global eradication of tuberculosis lies in the long duration of treatment required for cure. This well documented need for long-term therapy is historically attributed to the infecting mycobacteria becoming dormant within the host so that they are no longer killed by currently used antitubercular drugs that target actively growing bacteria. The dormancy model of tolerance has been the center of antitubercular drug research with the pursuit of drugs to target bacterial determinants that are expressed in the nonreplicating phase of infection. My PhD dissertation research determined that replicating bacteria become tolerant to multiple antitubercular agents upon macrophage residence through the induction of distinct efflux pumps that are also required for intracellular growth. My findings provide a mechanistic explanation for the clinical tuberculosis treatment data gathered over the last 50 years where the length of treatment required for cure correlates with bacterial burdens. Moreover, the addition of the calcium channel blocker, verapamil reverses this tolerance to the front-line drugs, isoniazid and rifampicin. If the tolerance mechanism revealed by my work is indeed a substantial contributor to the tolerance of active tuberculosis, then the addition of efflux pump inhibitors such as verapamil to the current antitubercular regimen should shorten the course of curative therapy. |
