Open AccessDiscovery of a compound which acts as a bacterial UMP kinase PyrH inhibitor
Author(s) -
Yoshida Tatsuhiko,
Nasu Hatsumi,
Namba Eiko,
Ubukata Osamu,
Yamashita Makoto
Publication year - 2012
Publication title -
fems microbiology letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.899
H-Index - 151
eISSN - 1574-6968
pISSN - 0378-1097
DOI - 10.1111/j.1574-6968.2012.02546.x
Subject(s) - streptococcus pneumoniae , bacteria , haemophilus influenzae , microbiology and biotechnology , biology , genetics
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 ( RTI s). 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‐(9 H ‐xanthen‐9‐ylacetylamino)phenyl]‐1‐cyclohexylmethylpropoxycarbonyloxy}acetate). PYRH ‐1 inhibits PyrH derived from both S treptococcus pneumoniae and H aemophilus 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 RTI s, such as S . pneumoniae , S taphylococcus 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 .