A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc²6230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC₅₀, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.

已经研究了一组19种恶二唑酮（OX）衍生物对两种致病的缓慢生长的分枝杆菌海洋分枝杆菌和牛分枝杆菌BCG以及无毒结核分枝杆菌（M. tb）mc ² 6230的抗分枝杆菌活性。令人鼓舞的最小抑菌浓度获得的（MIC）值促使我们测试它们在肉汤培养基中或巨噬细胞中是否针对有毒的M.tb H37Rv生长。的OX化合物显示动作的多样性，并发现对细胞外作用或者结核分枝杆菌的生长仅与主持MIC ₅₀，或在感染的巨噬细胞上以及在细胞外均在细菌生长上都处于细胞内。令人感兴趣的是，所有OX衍生物对宿主巨噬细胞均显示出非常低的毒性。在六个潜在OXS识别HPOX，细胞外的选择性抑制剂的结核分枝杆菌的生长，选择和进一步在竞争性标记对基于活动的探针脱硫生物素-FP /富集测定中，使用以鉴定其假定目标（一个或多个）。这种方法与质谱相结合，确定了18种可能的候选物，它们都是结核分枝杆菌中涉及的丝氨酸或半胱氨酸酶。脂质代谢和/或细胞壁生物合成。其中，的Ag85A，CAEA，TESA，笠和元已经报道了作为必须为在体外生长的结核分枝杆菌和/或它的生存和持久性巨噬细胞内。总的来说，我们的发现支持以下假设：OX衍生物可能代表一类新型的多靶点抑制剂，可通过累积抑制各种重要生理学中涉及的大量含Ser和Cys的酶而导致结核分枝杆菌生长的停止流程。