Aix-Marseille Univ., CNRS, LISM, Institut de Microbiologie de La Méditerranée FR3479, Marseille, France.
Department of Chemistry and Biochemistry, University of Missouri-St. Louis, One University Boulevard, St. Louis, Missouri, 63121, United States.
Eur J Med Chem. 2021 Jan 1;209:112908. doi: 10.1016/j.ejmech.2020.112908. Epub 2020 Oct 12.
Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drug-resistant mycobacteria for which standardized chemotherapeutic regimens are still lacking. Together the emergence of M. tb and M. abscessus multi-drug resistant strains with ineffective and expensive therapeutics, have paved the way to the development of new classes of anti-mycobacterial agents offering additional therapeutic options. In this context, specific inhibitors of mycobacterial lipolytic enzymes represent novel and promising antibacterial molecules to address this challenging issue. The results highlighted here include a complete overview of the antibacterial activities, either in broth medium or inside infected macrophages, of two families of promising and potent anti-mycobacterial multi-target agents, i.e. oxadiazolone-core compounds (OX) and Cyclophostin & Cyclipostins analogs (CyC); the identification and biochemical validation of their effective targets (e.g., the antigen 85 complex and TesA playing key roles in mycolic acid metabolism) together with their respective crystal structures. To our knowledge, these are the first families of compounds able to target and impair replicating as well as intracellular bacteria. We are still impelled in deciphering their mode of action and finding new potential therapeutic targets against mycobacterial-related diseases.
结核病（TB）由结核分枝杆菌（M. tb）引起，仍然是全球最致命的传染病，2018 年有 150 万人因此死亡，其中约 15%归因于耐药菌株。另一个重要的例子是非结核分枝杆菌（NTM）中的脓肿分枝杆菌（M. abscessus），它可引起皮肤和肺部感染，占囊性纤维化（CF）患者中 NTM 感染的 95%。M. abscessus 是一种新的临床相关病原体，被认为是最耐药的分枝杆菌之一，目前仍然缺乏标准化的化疗方案。结核分枝杆菌和脓肿分枝杆菌耐药菌株的出现，加上无效且昂贵的治疗方法，为开发新类别的抗分枝杆菌药物铺平了道路，这些药物为治疗提供了更多的选择。在这种情况下，分枝杆菌脂酶的特异性抑制剂代表了一种新的、有前途的抗菌分子，可以解决这一具有挑战性的问题。这里强调的结果包括两种有前途和有效的抗分枝杆菌多靶标药物，即恶唑二酮核化合物（OX）和环孢菌素和环孢菌素类似物（CyC），在肉汤培养基或感染的巨噬细胞中，其抗菌活性的全面概述；鉴定和生化验证它们的有效靶点（例如，抗原 85 复合物和在分枝酸代谢中起关键作用的 TesA）及其各自的晶体结构。据我们所知，这些是第一批能够靶向和破坏复制和细胞内细菌的化合物家族。我们仍在努力破译它们的作用机制，并寻找针对分枝杆菌相关疾病的新的潜在治疗靶点。
