Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju, South Korea.
Department of Clinical Laboratory Science, Semyung University, Jecheon, South Korea.
PLoS One. 2018 Apr 26;13(4):e0195595. doi: 10.1371/journal.pone.0195595. eCollection 2018.
Mycobacterium abscessus is a rapidly growing life-threatening mycobacterium with multiple drug-resistance mechanisms. However, there is no official regimen for M. abscessus therapy. In this study, we screened the Pathogen Box, which contains 400 drug-like molecules active against neglected diseases, to identify active molecules targeting Mycobacterium abscessus using resazurin live/dead assays. In this screening assay, the Z-factor was 0.7, as an indicator of the statistical confidence of the assay. A cut-off of 80% growth inhibition in the screening resulted in the identification of four different compounds at a single concentration (20 μM). Dose-response curves identified three different hit candidates, i.e., MMV688508, MMV688844, and MMV688845, which generated good inhibitory curves. All hit candidates were expected to have different molecular targets. Among them, MMV688844 showed the best minimum inhibitory concentration value for not only wild-type M. abscessus but also for nine different R and S morphotype clinical isolates. Thus, we found that MMV688844, identified from the Pathogen Box screen, may be a promising candidate in the M. abscessus drug discovery pipeline.
脓肿分枝杆菌是一种快速生长的、危及生命的分枝杆菌，具有多种耐药机制。然而，目前还没有针对脓肿分枝杆菌治疗的标准方案。在这项研究中，我们筛选了病原体库，其中包含 400 种针对被忽视疾病的类药分子，使用 Resazurin 活/死检测法来鉴定针对脓肿分枝杆菌的活性分子。在该筛选测定中，Z 因子为 0.7，这是测定统计学置信度的指标。在筛选中，以 80%的生长抑制作为单一浓度（20 μM）的四个不同化合物的鉴定界限。剂量反应曲线鉴定出三种不同的命中候选物，即 MMV688508、MMV688844 和 MMV688845，它们产生了良好的抑制曲线。所有命中候选物都有望具有不同的分子靶标。其中，MMV688844 不仅对野生型脓肿分枝杆菌，而且对 9 种不同 R 和 S 形态临床分离株均显示出最佳的最小抑菌浓度值。因此，我们发现从病原体库筛选出的 MMV688844 可能是脓肿分枝杆菌药物发现管道中的一个有前途的候选物。
