Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

Significance Most of the Mycobacterium tuberculosis (Mtb) bacilli in the sputum of most patients with tuberculosis studied to date do not grow on standard agar-based media but rather grow when diluted in liquid media of similar composition. Here, we describe a rigorously standardized and independently replicated method to generate and count these differentially detectable (DD) Mtb in culture. DD Mtb generation required the action of a rifamycin on RNA polymerase after induction of phenotypic tolerance. Generation of these cells in vitro led to identification of one drug that can kill them and should facilitate the discovery of others.