Brucella suis histidinol dehydrogenase: synthesis and inhibition studies of a series of substituted benzylic ketones derived from histidine.
Brucella spp. is the causative agent of brucellosis (Malta fever), which is the most widespread zoonosis worldwide. The pathogen is capable of establishing persistent infections in humans which are extremely difficult to eradicate even with antibiotic therapy. Moreover, Brucella is considered as a potential bioterrorism agent. Histidinol dehydrogenase (HDH, EC 1.1.1.23) has been shown to be essential for the intramacrophagic replication of this pathogen. It therefore constitutes an original and novel target for the development of anti-Brucella agents. In this work, we cloned and overexpressed the HDH-encoding gene from Brucella suis, purified the protein and evidenced its biological activity. We then investigated the inhibitory effects of a series of substituted benzylic ketones derived from histidine. Most of the compounds reported here inhibited B. suis HDH in the lower nanomolar range and constitute attractive candidates for the development of novel anti-Brucella agents.
Abdo
Marie-Rose
MR
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Joseph
Pascale
P
Boigegrain
Rose-Anne
RA
Liautard
Jean-Pierre
JP
Montero
Jean-Louis
JL
Köhler
Stephan
S
Winum
Jean-Yves
JY
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001937:Brassica / Q000201:enzymology; D041021:Brucella suis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*
D001426:Bacterial Proteins; D001593:Benzyl Compounds; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007659:Ketones; D006639:Histidine; D000429:Alcohol Oxidoreductases; C021358:histidinol dehydrogenase