Faïon Léo, Djaout Kamel, Pintiala Catalin, Piveteau Catherine, Leroux Florence, Biela Alexandre, Slupek Stéphanie, Antoine Rudy, Záhorszká Monika, Cantrelle Francois-Xavier, Hanoulle Xavier, Korduláková Jana, Deprez Benoit, Willand Nicolas, Baulard Alain R, Flipo Marion
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000 Lille, France.
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.
Pharmaceuticals (Basel). 2023 Feb 22;16(3):335. doi: 10.3390/ph16030335.
, the pathogen that causes tuberculosis, is responsible for the death of 1.5 million people each year and the number of bacteria resistant to the standard regimen is constantly increasing. This highlights the need to discover molecules that act on new targets. Mycolic acids, which are very long-chain fatty acids essential for viability, are synthesized by two types of fatty acid synthase (FAS) systems. MabA (FabG1) is an essential enzyme belonging to the FAS-II cycle. We have recently reported the discovery of anthranilic acids as MabA inhibitors. Here, the structure-activity relationships around the anthranilic acid core, the binding of a fluorinated analog to MabA by NMR experiments, the physico-chemical properties and the antimycobacterial activity of these inhibitors were explored. Further investigation of the mechanism of action showed that these compounds affect other targets than MabA in mycobacterial cells and that their antituberculous activity is due to the carboxylic acid moiety which induces intrabacterial acidification.
导致结核病的病原体每年造成150万人死亡，并且对标准治疗方案耐药的细菌数量在不断增加。这凸显了发现作用于新靶点的分子的必要性。分枝菌酸是维持生存能力所必需的非常长链脂肪酸，由两种脂肪酸合酶（FAS）系统合成。MabA（FabG1）是FAS-II循环中的一种必需酶。我们最近报道了发现邻氨基苯甲酸作为MabA抑制剂。在此，研究了邻氨基苯甲酸核心周围的构效关系、通过核磁共振实验一种氟化类似物与MabA的结合、这些抑制剂的物理化学性质和抗分枝杆菌活性。对作用机制的进一步研究表明，这些化合物在分枝杆菌细胞中影响的靶点并非MabA，并且它们的抗结核活性归因于诱导细菌内酸化的羧酸部分。
