Journal
FRONTIERS IN MICROBIOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2020.553962
Keywords
tuberculosis; CHK2; host-directed therapy; kinase inhibitor; screen
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Funding
- Canadian Institutes for Health Research [CIHR PJT-148646, PJT-152931]
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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 ofMycobacterium tuberculosis(M.tb). Screen validity was confirmed internally by aZ ' = 0.5 and externally by detecting previously reported host-targeting anti-M.tbcompounds. 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.tbcompound. CHK2 inhibition by RNAi phenocopied the intracellular inhibitory effect of DDUG. DDUG was active intracellularly againstM.tb, but not other mycobacteria. DDUG also had extracellular activity against 4 of 12 bacteria tested, includingM.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.tbcompounds.
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