Screening-based discovery of the first novel ATP competitive inhibitors of the Staphylococcus aureus essential enzyme UMP kinase.
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.
['Doig|Peter|P|', 'Gorseth|Elise|E|', 'Nash|Tory|T|', 'Patten|Arthur|A|', 'Gao|Ning|N|', 'Blackett|Carolyn|C|']
D000255:Adenosine Triphosphate D004353:Drug Evaluation, Preclinical D057075:Enzyme Assays D004791:Enzyme Inhibitors D057166:High-Throughput Screening Assays D007700:Kinetics D008826:Microbial Sensitivity Tests D009703:Nucleoside-Phosphate Kinase D011743:Pyrimidines D015203:Reproducibility of Results D013211:Staphylococcus aureus
Inhibitor UMP kinase PyrH Screening HTS Antibacterial targets