Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

Dong Yang (1) , Guy Vandenbussche (1) , Didier Vertommen (2) , Damien Evrard (2) , Romany Abskharon (3) , Jean-François Cavalier (4) , Gilles Berger (1) , Stéphane Canaan (4) , Mohammad Shahneawz Khan (2) , Sheng Zeng (1) , Alexandre Wohlkonig (3) , Martine Prévost (1) , Patrice Soumillion (2) , Véronique Fontaine (1)

1 ULB - Université libre de Bruxelles
2 UCL - Université Catholique de Louvain = Catholic University of Louvain
3 VUB - Vrije Universiteit Brussel
4 LISM - Laboratoire d'ingénierie des systèmes macromoléculaires

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 arachi-donyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with van-comycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.

Mots clés: methyl arachidonyl fluorophosphonate; Mycobacterium tuberculosis; TesA; tetrahydrolipstatin; vancomycin

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire; Biologie structurale [q-bio.BM]

Dong Yang, Guy Vandenbussche, Didier Vertommen, Damien Evrard, Romany Abskharon, et al.. Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility. FEBS Letters, 2019, ⟨10.1002/1873-3468.13555⟩. ⟨hal-02276161⟩