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A screen of a eukaryotic kinase inhibitor library in an established intracellular infection model identified a set of drug candidates enabling intracellular killing of  Mycobacterium tuberculosis  ( M.tb ). Screen validity was confirmed internally by a  Z ′ = 0.5 and externally by detecting previously reported host-targeting anti- M.tb  compounds. Inhibitors of the CHK kinase family, specifically checkpoint kinase 2 (CHK2), showed the highest inhibition and lowest toxicity of all kinase families. The screen identified and validated DDUG, a CHK2 inhibitor, as a novel bactericidal anti- M.tb  compound. CHK2 inhibition by RNAi phenocopied the intracellular inhibitory effect of DDUG. DDUG was active intracellularly against  M.tb , but not other mycobacteria. DDUG also had extracellular activity against 4 of 12 bacteria tested, including  M.tb . Combined, these observations suggest DDUG acts in tandem against both host and pathogen. Importantly, DDUG’s validation highlights the screening and analysis methodology developed for this screen, which identified novel host-directed anti- M.tb  compounds.

High-Content Screening of Eukaryotic Kinase Inhibitors Identify CHK2 Inhibitor Activity Against Mycobacterium tuberculosis