Screening-based discovery of the first novel ATP competitive inhibitors of the Staphylococcus aureus essential enzyme UMP kinase

Biochem Biophys Res Commun. 2013 Jul 19;437(1):162-7. doi: 10.1016/j.bbrc.2013.06.060. Epub 2013 Jun 24.

Abstract

UMP kinase (PyrH) is an essential enzyme found only in bacteria, making it ideal as a target for the discovery of antibacterials. To identify inhibitors of PyrH, an assay employing Staphylococcus aureus PyrH coupled to pyruvate kinase/lactate dehydrogenase was developed and was used to perform a high throughput screen. A validated aminopyrimidine series was identified from screening. Kinetic characterization of this aminopyrimidine indicated it was a competitive inhibitor of ATP. We have shown that HTS can be used to identify potential leads for this novel target, the first ATP competitive inhibitor of PyrH reported.

Keywords: Antibacterial targets; HTS; Inhibitor; PyrH; Screening; UMP kinase.

MeSH terms

  • Adenosine Triphosphate / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Assays
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Kinetics
  • Microbial Sensitivity Tests
  • Nucleoside-Phosphate Kinase / antagonists & inhibitors*
  • Nucleoside-Phosphate Kinase / metabolism
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Reproducibility of Results
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / enzymology*

Substances

  • Enzyme Inhibitors
  • Pyrimidines
  • Adenosine Triphosphate
  • uridine monophosphate kinase
  • Nucleoside-Phosphate Kinase
  • pyrimidine