Discovery of a compound which acts as a bacterial UMP kinase PyrH inhibitor
| Autor: | Osamu Ubukata, Hatsumi Nasu, Makoto Yamashita, Tatsuhiko Yoshida, Eiko Namba |
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| Rok vydání: | 2012 |
| Předmět: |
Staphylococcus aureus
Pyrimidine Allosteric regulation Microbial Sensitivity Tests Microbiology Uridine Diphosphate chemistry.chemical_compound Inhibitory Concentration 50 Genetics Humans Enzyme Inhibitors Mode of action Molecular Biology IC50 UMP kinase biology Kinase Surface Plasmon Resonance biology.organism_classification Antimicrobial Haemophilus influenzae Streptococcus pneumoniae chemistry Biochemistry Nucleoside-Phosphate Kinase Uridine Monophosphate Bacteria Protein Binding |
| Zdroj: | FEMS microbiology letters. 330(2) |
| ISSN: | 1574-6968 |
| Popis: | PyrH is a member of the UMP kinase family that catalyses the conversion of UMP to UDP, an essential step in the pyrimidine metabolic pathway in a variety of bacteria including those causing community-acquired respiratory tract infections (RTIs). In this study, we have developed a luminescence-based kinase assay of PyrH and evaluated the inhibitory activity of PYRH-1 (sodium {3-[4-tert-butyl-3-(9H-xanthen-9-ylacetylamino)phenyl]-1-cyclohexylmethylpropoxycarbonyloxy}acetate). PYRH-1 inhibits PyrH derived from both Streptococcus pneumoniae and Haemophilus influenzae with IC(50) (concentration of inhibitor giving a 50% decrease in enzyme activity) values of 48 and 75 μM, respectively, whose inhibitory activity against S. pneumoniae PyrH was far higher compared with that of UTP (IC(50) = 710 μM), an allosteric PyrH inhibitor. The molecular interaction analysis by surface plasmon resonance suggested that PYRH-1 directly interacts with S. pneumoniae PyrH at one-to-one molar ratio. Finally, PYRH-1 was shown to have antimicrobial activity against several different bacteria causing RTIs, such as S. pneumoniae, Staphylococcus aureus, H. influenzae (acrA knockout strain), suggesting that PYRH-1 is a prototype chemical compound that can be harnessed as an antimicrobial drug with a novel mode of action by targeting bacterial PyrH. |
| Databáze: | OpenAIRE |
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