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.

在已建立的细胞内感染模型中，真核激酶抑制剂文库的筛选确定了一组候选药物，可实现细胞内杀伤性 结核分枝杆菌 （结核菌）。屏幕有效性由内部确认ž” = 0.5，并通过检测先前报道的针对宿主的抗结核菌化合物。CHK激酶家族的抑制剂，特别是检查点激酶2（CHK2），在所有激酶家族中均表现出最高的抑制作用和最低的毒性。该筛查确定并验证了CHK2抑制剂DDUG作为一种新型的杀菌抗结核菌复合。RNAi对CHK2的抑制表现出DDUG的细胞内抑制作用。DDUG在细胞内对结核菌，但其他分枝杆菌则没有。DDUG还具有针对12种受测细菌中的4种的细胞外活性，包括结核菌。综上，这些观察结果表明DDUG协同作用于宿主和病原体。重要的是，DDUG的验证突出显示了为此筛选开发的筛选和分析方法，该方法确定了新型的宿主定向抗结核菌 化合物。