COMBATTB · Comprehensive Mechanisms of Bacterial Antibiotic Tolerance in Mycobacterium Tuberculosis

Mycobacterium tuberculosis (Mtb) is one of about a dozen bacterial species for which some clinical isolates are now resistant to most or all antibiotics (abx) approved for treatment of the infections they cause. Mechanisms of antimicrobial resistance (AMR) in Mtb deserve study for their potential relevance to AMR in other pathogens; because tuberculosis (TB) is now the leading cause of death from infectious disease; and because drug-resistant TB may be the most prevalent of all drug-resistant bacterial infections. Heritable AMR in Mtb emerges with interruption of treatment, and the long duration of TB treatment provides many opportunities for interruption. Prolonged treatment is necessary because of nonheritable resistance, also called phenotypic tolerance or persistence, defined as the transient tolerance of bacteria in an antibiotic-sensitive population to an antibiotic during exposure to an otherwise lethal concentration of that antibiotic. In contrast to “resisters”, whose AMR is genetically encoded, “persisters” are genetically sensitive bacteria whose phenotypic tolerance allows them to survive for prolonged periods during what would otherwise be rapidly curative treatment. In addition, phenotypic tolerance is likely a source of treatment failure and a major contributor to TB reactivation after apparently effective treatment. The specific aims of this application are to identify genetic determinants that foster phenotypic tolerance in Mtb and decipher at a molecular level the mechanisms by which Mtb enters and maintains a persistent state.