Home
Many of the most effective antibiotics target fundamental pathways such as, bacterial cell wall biosynthesis, DNA replication and protein biosynthesis.
Mur ligase are a set of four Mur ubiquitin ligase enzymes: MurC, MurD, MurE, MurF which catalyze the addition of a short polypeptide to UDP-D-acetylmuramic acid in the process of bacterial cell wall buildup from peptidoglycans.
All four enzymes are topologically similar.
- MurC ligase or UDP-N-acetylmuramoyl-L-alanine ligase adds L-alanine to peptidoglycans.
- MurD ligase or UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase catalyzes the conversion of UDP-N-acetylmuramoyl-L-alanine (UMA), D-glutamate and ATP to UDP-N-acetylmuramoyl-L-alanine-D-glutamate and ADP. I.e. adds D-glutamate to peptidoglycans.
- MurE ligase or UDP-N-acetylmuramoyl-L-alaninyl-D-glutamate-2,6-diaminopimelate ligase adds meso-diaminpimelate to peptidoglycans.
- MurF ligase or UDP-N-acetylmuramoyl-L-alanine-D-glutamyl-lysine-D-alanyl-D-alanine ligase adds D-alanyl-D-alanine to peptidoglycans.
To be added
To be added
Novel Pyrazolopyrimidine based inhibitors of Pseudomonas aeruginosa MurC have been reported CHEMBL3355659 derived from a high-throughput screening hit DOI.
Radio-labeled precursor incorporation showed these compounds selectively inhibited peptidoglycan biosynthesis, and genetic studies confirmed the target of pyrazolopyrimidines to be MurC. CHEMBL3355659 was a potent enzyme inhibitor IC50 0.001 uM, but showed poor against wild-type bacteria. However it showed appreciable antibacterial activity against efflux-deficient mutants.
MRCt (LifeArc) have developed an HTS for MurC and identified hits. These hits were poorly soluble, though possessing in vitro activity had no antibacterial activity.
X-chem screen, run by Dom Bellini. Re-screening? 4 hits on Fragalysis? Ian Gilbert says they are not tractable for elaboration, so is doing a new NMR screen. There have been 3-4 other frag screens, but not known? PaulB has already found a decent way to go
On Fragalysis?
No hits reported. But has been done by LifeArc in the last year (NMR Leicester? Not Xchem?). Dom Bellini can make them available, or not?
CHEMBL3355659 InChiKey = MOLGZLFXZJMRCB-OAHLLOKOSA-N