Frontiers in Microbiology (Sep 2020)

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

  • Tirosh Shapira,
  • Leah Rankine-Wilson,
  • Joseph D. Chao,
  • Virginia Pichler,
  • Celine Rens,
  • Tom Pfeifer,
  • Yossef Av-Gay,
  • Yossef Av-Gay

DOI
https://doi.org/10.3389/fmicb.2020.553962
Journal volume & issue
Vol. 11

Abstract

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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.

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