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Methyl Arachidonyl Fluorophosphonate Inhibits Mycobacterium Tuberculosis Thioesterase TesA and Globally Affects Vancomycin Susceptibility

Dong Yang, Guy Vandenbussche, Didier Vertommen, Damien Evrard, Romany Abskharon, Jean-François Cavalier, Gilles Berger, Stéphane Canaan, Mohammad Shahneawz Khan, Sheng Zeng, Alexandre Wohlkönig, Martine Prévost, etc.

FEBS Lett. 2020 Jan;594(1):79-93.

PMID: 31388991

Abstract:

Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements of Mycobacterium tuberculosis, in particular because of their involvement in cell wall impermeability and drug resistance. The biosynthesis of these waxy lipids involves multiple enzymes, including thioesterase A (TesA). We observed that purified recombinant M. tuberculosis TesA is able to dimerize in the presence of palmitoyl-CoA and our 3D structure model of TesA with this acyl-CoA suggests hydrophobic interaction requirement for dimerization. Furthermore, we identified that methyl arachidonyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR424774 Methyl arachidonyl fluorophosphonate Methyl arachidonyl fluorophosphonate Price
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