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

Abstract

Edited by Peter BrzezinskiPhthiocerol 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.

Antimycobacterial Activities of Hydroxamic Acids and Their Iron(II/III), Nickel(II), Copper(II) and Zinc(II) Complexes

“…The fixed concentrations were 4-and 20-fold lower than the MIC a or MIC b , respectively. In agreement with the checkerboard method, synergy is reached when the FICI is <0.5 [21].…”

A screen of covalent inhibitors in Mycobacterium tuberculosis identifies serine hydrolases involved in lipid metabolism as potential therapeutic targets

“…TesA is a critical virulence factor due to its necessity for the synthesis of PDIM. In addition, tesA mutants show increased susceptibility to antibiotics (Bellerose et al, 2020; Chavadi et al, 2011; Yang et al, 2020), presumably due to the increased permeability of PDIM-deficient cells. The fact that our wild-type strain contains a mutation in ppsA is serendipitous because it allows us to decouple the effects of TesA and other SH inhibition from the general increased sensitivity due to PDIM deficiency.…”

Mycobacterium tuberculosis Requires the Outer Membrane Lipid Phthiocerol Dimycocerosate for Starvation-Induced Antibiotic Tolerance

“…This could dramatically shorten TB treatment times and prevent emergence of new drug-resistant strains. PDIM biosynthesis is a complex process, requiring multiple polyketide synthases, fatty acyl ligases, and thioesterases, several of which have already been explored as potential drug targets ( 59 , 75 , 76 ). It will be critical to determine whether PDIM deficiency also increases M. tuberculosis antibiotic susceptibility during infection to further support development of new inhibitors targeting PDIM production, which we intend to pursue in our future studies.…”