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

Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements ofMycobacterium  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 recombinantM.  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 antimicrob ial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Article Source Type: research