Assessment of Pseudomonas aeruginosa N5,N10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase as a potential antibacterial drug target.

PloS One
Thomas C EadsforthWilliam N Hunter

Abstract

The bifunctional enzyme methylenetetrahydrofolate dehydrogenase - cyclohydrolase (FolD) is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Å resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biologi...Continue Reading

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Citations

Feb 18, 2014·Acta Crystallographica. Section D, Biological Crystallography·Vadim RimsaWilliam N Hunter
Jan 9, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Lucille MoynieGunter Schneider
Mar 23, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Vincenzo A RaoWilliam N Hunter
Jun 1, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Alice DawsonWilliam N Hunter
Aug 29, 2018·ChemMedChem·Gregorio CulliaAndrea Pinto
Mar 7, 2019·Acta Crystallographica. Section F, Structural Biology Communications·Renata BuenoWilliam N Hunter
Oct 21, 2015·BMC Microbiology·Rasmus Lykke MarvigHelle Krogh Johansen
Sep 4, 2020·Molecular Cancer Therapeutics·Aamod S DekhneLarry H Matherly

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Methods Mentioned

BETA
differential scanning fluorimetry
surface plasmon resonance
PCR
chip
gel filtration
size exclusion gel chromatography

Software Mentioned

LSQKAB
ICM Pro
Molsoft
FolD
Scrubber
Ec
PyMOL
BioLogic
Pa
COOT

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