Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening

• Published in: European journal of medicinal chemistry 2020-08, Vol.200, p.112440, Article 112440
• Main Authors: Faïon, Léo, Djaout, Kamel, Frita, Rosangela, Pintiala, Catalin, Cantrelle, Francois-Xavier, Moune, Martin, Vandeputte, Alexandre, Bourbiaux, Kevin, Piveteau, Catherine, Herledan, Adrien, Biela, Alexandre, Leroux, Florence, Kremer, Laurent, Blaise, Mickael, Tanina, Abdalkarim, Wintjens, René, Hanoulle, Xavier, Déprez, Benoit, Willand, Nicolas, Baulard, Alain R., Flipo, Marion
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Biochemistry; Biochemistry, Molecular Biology; Chemical Sciences; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; FabG1; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - metabolism; Fragment; Life Sciences; MabA inhibitors; Molecular Structure; Mycobacterium tuberculosis - enzymology; Mycolic acid; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Structural Biology; Structure-Activity Relationship; Tuberculosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112440

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments. [Display omitted] •Fragment-based screening to discover the first MabA (FabG1) inhibitors.•Development of a new LC-MS/MS based enzymatic assay.•19F ligand-observed NMR experiment to confirm the direct binding of the inhibitors to MabA.