Models of nonreplication help us understand the biology of persistent Mycobacterium tuberculosis. High throughput screening (HTS) against nonreplicating M. tuberculosis may lead to identification of tool compounds that affect pathways on which bacterial survival depends in such states and to development of drugs that can overcome phenotypic resistance to conventional antimycobacterial agents, which are mostly active against replicating M. tuberculosis. We describe a multistress model of nonreplication that mimics some of the microenvironmental conditions that M. tuberculosis faces in the host as adapted for HTS. The model includes acidic pH, mild hypoxia, a flux of nitric oxide, and other reactive nitrogen intermediates arising from nitrite at low pH and low concentrations of a fatty acid (butyrate) as a carbon source.
Keywords: Acidic pH; Antibiotics; Fatty acids; High-throughput screening; Hypoxia; Mycobacterium tuberculosis; Nitric oxide; Nonreplication; Phenotypic tolerance; Reactive nitrogen species.