Inhibitory Evaluation of αPMM/PGM from Pseudomonas aeruginosa: Chemical Synthesis, Enzyme Kinetics, and Protein Crystallographic Study

J Org Chem. 2019 Aug 2;84(15):9627-9636. doi: 10.1021/acs.joc.9b01305. Epub 2019 Jul 16.

Abstract

α-Phosphomannomutase/phosphoglucomutase (αPMM/PGM) from P. aeruginosa is involved in bacterial cell wall assembly and is implicated in P. aeruginosa virulence, yet few studies have addressed αPMM/PGM inhibition from this important Gram-negative bacterial human pathogen. Four structurally different α-d-glucopyranose 1-phosphate (αG1P) derivatives including 1-C-fluoromethylated analogues (1-3), 1,2-cyclic phosph(on)ate analogues (4-6), isosteric methylene phosphono analogues (7 and 8), and 6-fluoro-αG1P (9), were synthesized and assessed as potential time-dependent or reversible αPMM/PGM inhibitors. The resulting kinetic data were consistent with the crystallographic structures of the highly homologous Xanthomonas citri αPGM with inhibitors 3 and 7-9 binding to the enzyme active site (1.65-1.9 Å). These structural and kinetic insights will enhance the design of future αPMM/PGM inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Phosphoglucomutase / antagonists & inhibitors*
  • Phosphoglucomutase / metabolism
  • Phosphotransferases (Phosphomutases) / antagonists & inhibitors*
  • Phosphotransferases (Phosphomutases) / metabolism
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / enzymology
  • Sugar Phosphates / chemical synthesis
  • Sugar Phosphates / chemistry
  • Sugar Phosphates / pharmacology*

Substances

  • Enzyme Inhibitors
  • Sugar Phosphates
  • alpha-D-glucopyranose 1-phosphate
  • Phosphotransferases (Phosphomutases)
  • Phosphoglucomutase
  • phosphomannomutase