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FEBS Lett. 2019 Aug 7. doi: 10.1002/1873-3468.13555. [Epub ahead of print]

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

Author information

1
Microbiology, Bioorganic and Macromolecular Chemistry Unit, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), 1050, Brussels, Belgium.
2
Laboratory for the Structure and Function of Biological Membranes, Faculty of Sciences, Université Libre de Bruxelles (ULB), 1050, Brussels, Belgium.
3
de Duve Institute, Université catholique de Louvain (UCL), 1200, Brussels, Belgium.
4
Biochemistry and Genetics of Microorganisms, Louvain Institute of Biomolecular Science and Technology, Université catholique de Louvain (UCL), 1348, Louvain-la-Neuve, Belgium.
5
National Institute of Oceanography and Fisheries (NIOF), 11516, Cairo, Egypt.
6
VIB-VUB Center for Structural Biology, Vrije Universiteit Brussel (VUB), 1050, Brussels, Belgium.
7
Aix-Marseille University, CNRS, LISM, IMM FR3479, Marseille, France.

Abstract

Phthiocerol dimycocerosates (PDIM) 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 (MAFP), 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 anti-tuberculous drug candidates. This article is protected by copyright. All rights reserved.

KEYWORDS:

Mycobacterium tuberculosis ; Methyl arachidonyl fluorophosphonate; TesA; Tetrahydrolipstatin; Vancomycin

PMID:
31388991
DOI:
10.1002/1873-3468.13555

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