Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects
Dong Yang1, Guy Vandenbussche2, Didier Vertommen3
1Microbiology, Bioorganic and Macromolecular Chemistry Unit, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Belgium.
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.
Insights
Mycobacterium tuberculosis thioesterase A (TesA) dimerizes with palmitoyl-CoA. Inhibiting TesA shows synergistic activity with vancomycin, suggesting TesA inhibitors as potential tuberculosis drug candidates.
Area of Science:
- Biochemistry
- Microbiology
- Drug Discovery
Background:
- Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are key virulence factors in Mycobacterium tuberculosis, contributing to cell wall integrity and drug resistance.
- The biosynthesis of these lipids involves essential enzymes like thioesterase A (TesA).
Purpose of the Study:
- To investigate the biochemical properties and potential drug development targeting of Mycobacterium tuberculosis thioesterase A (TesA).
Main Methods:
- Purification and characterization of recombinant M. tuberculosis TesA.
- 3D structure modeling of TesA in complex with palmitoyl-CoA.
- Assessment of TesA inhibition using methyl arachidonyl fluorophosphonate and synergistic antimicrobial activity with vancomycin.
Main Results:
- Purified recombinant M. tuberculosis TesA was observed to dimerize in the presence of palmitoyl-CoA.
- 3D structure modeling indicated that hydrophobic interactions are crucial for TesA dimerization.
- Methyl arachidonyl fluorophosphonate, a TesA inhibitor, demonstrated synergistic antimicrobial effects when combined with vancomycin.
Conclusions:
- TesA dimerization is influenced by palmitoyl-CoA and hydrophobic interactions.
- Targeting TesA with inhibitors, such as methyl arachidonyl fluorophosphonate, shows promise for developing novel antitubercular therapies.
- The synergistic activity with vancomycin highlights the potential of TesA inhibitors in combating drug-resistant tuberculosis.
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