Exploring the Antitubercular Activity of Anthranilic Acid Derivatives: From MabA (FabG1) Inhibition to Intrabacterial Acidification

• Main Authors: Léo Faïon (Author), Kamel Djaout (Author), Catalin Pintiala (Author), Catherine Piveteau (Author), Florence Leroux (Author), Alexandre Biela (Author), Stéphanie Slupek (Author), Rudy Antoine (Author), Monika Záhorszká (Author), Francois-Xavier Cantrelle (Author), Xavier Hanoulle (Author), Jana Korduláková (Author), Benoit Deprez (Author), Nicolas Willand (Author), Alain R. Baulard (Author), Marion Flipo (Author)
• Format: Book
• Published: MDPI AG, 2023-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<i>Mycobacterium tuberculosis</i>, 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 <i>M. tuberculosis</i> targets. Mycolic acids, which are very long-chain fatty acids essential for <i>M. tuberculosis</i> 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 <i>in bacterio</i> 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.

Item Description

10.3390/ph16030335
1424-8247