One of the significant challenges to treat tuberculosis is the phenotypic resistance adapted by the latent or dormant Mycobacterium tuberculosis (M. tuberculosis) cells against most of the available drugs. Different in-vitro assay such as oxygen depletion model and nutrient starvation models have contributed to unravelling the pathogen phenotypic resistance but are too cumbersome for application to high-throughput screening (HTS) assays. In this context, non-replicating streptomycin-starved 18b (SS18b) mutant strain of M. tuberculosis provided a simple and reproducible model. This model mimics latent tuberculosis and is best suited for screening medicinally appropriate libraries. Using SS18b strain in a resazurin reduction microplate assay (REMA), high-throughput screening of ChemDiv library constituting of 30,000 compounds resulted in the identification of 470 active compounds. Clustering and scaffolding based medicinal chemistry analysis characterized these hits into 15 scaffolds. Seven most potent compounds exhibiting an MIC ≤ 1 μg/ml against SS18b were non-toxic in HepG2 cell line (selective Index ≥ 160). Our screening revealed seven novel compounds exhibiting activity against the non-replicating form of M tuberculosis. 8002-7516 was the most promising compound showing intracellular killing and could be optimized to develop a lead drug candidate.

中文翻译：

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以链霉素依赖性结核分枝杆菌 18b 株为模型，高通量筛选化合物库以鉴定针对潜伏结核分枝杆菌的新型抑制剂

治疗结核病的重大挑战之一是潜伏或休眠的结核分枝杆菌 (M.tuberculosis) 细胞对大多数可用药物产生的表型耐药性。不同的体外试验，如氧耗竭模型和营养饥饿模型，有助于阐明病原体表型抗性，但对于应用于高通量筛选 (HTS) 试验来说过于繁琐。在这种情况下，非复制性链霉素饥饿 18b (SS18b) 结核分枝杆菌突变株提供了一个简单且可重复的模型。该模型模拟潜伏性结核病，最适合用于筛选医学上合适的文库。在刃天青还原微孔板测定 (REMA) 中使用 SS18b 菌株，高通量筛选由 30 个组成的 ChemDiv 文库，000 种化合物导致鉴定出 470 种活性化合物。基于聚类和支架的药物化学分析将这些命中表征为 15 个支架。七种最有效的化合物对 SS18b 的 MIC ≤ 1 μg/ml，在 HepG2 细胞系中无毒（选择性指数≥ 160）。我们的筛选揭示了七种对非复制型结核分枝杆菌具有活性的新型化合物。8002-7516 是表现出细胞内杀伤作用的最有希望的化合物，可以优化以开发先导候选药物。我们的筛选揭示了七种对非复制型结核分枝杆菌具有活性的新型化合物。8002-7516 是表现出细胞内杀伤作用的最有希望的化合物，可以优化以开发先导候选药物。我们的筛选揭示了七种对非复制型结核分枝杆菌具有活性的新型化合物。8002-7516 是表现出细胞内杀伤作用的最有希望的化合物，可以优化以开发先导候选药物。