Biological Profiling Enables Rapid Mechanistic Classification of Phenotypic Screening Hits and Identification of KatG Activation-Dependent Pyridine Carboxamide Prodrugs With Activity Against Mycobacterium tuberculosis.

摘要: Compounds with novel modes of action are urgently needed to develop effective combination therapies for the treatment tuberculosis. In this study, a series compounds was evaluated activity against replicating Mycobacterium tuberculosis and Vero cell line toxicity. Fourteen in vitro activities low micrometer range favorable selectivity index were classified using reporter strains M. which showed that six interfered wall metabolism one disrupted DNA metabolism. Counter-screening carrying mutations promiscuous drug targets argued DprE1 MmpL3 as hits any actives eliminated cytochrome bc 1 complex target compounds. Instead, whole-genome sequencing spontaneous resistant mutants and/or counter-screening common isoniazid-resistant revealed four wall-active compounds, all pyridine carboxamide analogues, metabolized by KatG form InhA inhibitors. Resistance two these associated katG did not confer cross-resistance isoniazid. Of remaining seven low-level resistance an inactivating mutation Rv0678, regulator MmpS5-MmpL5 system, has been implicated non-specific efflux multiple chemotypes. Another mapped mycothiol-dependent reductase, Rv2466c, suggesting prodrug mechanism case. The inability isolate suggests they act via mechanisms have yet be elucidated.