title: Screening of Actinobacillus pleuropneumoniae LuxS inhibitors.
abstract: LuxS, a conserved bacterial enzyme involved in the activated methyl cycle, catalyzes S-ribosylhomocysteine (SRH) into homocysteine and AI-2 (the inter-species quorum-sensing signal molecule). This enzyme has been reported to be essential for the survival of Actinobacillus pleuropneumoniae in its natural host. Therefore, it is a potential drug target against A. pleuropneumoniae, an important swine respiratory pathogen causing great economic losses in the pig industry worldwide. In this study, the enzymatic activity determination method was established using the recombinant LuxS of A. pleuropneumoniae. Thirty-five compounds similar to the shape of SRH were screened from the Specs compound library by the software vROCS and were evaluated for LuxS inhibition. Three compounds could inhibit LuxS activity. Two of them were confirmed to be competitive inhibitors and the third one was uncompetitive. All the three compounds displayed inhibitory effects on the growth of A. pleuropneumoniae and two other important swine pathogens, Haemophilis parasuis and Streptococcus suis, with MIC50 values ranging from 11 to 51 μg/ml. No significant cytotoxic effect of the compounds was detected on porcine PK-15 cells at the concentration which showed inhibitory effect on bacterial growth. These results suggest that LuxS is an ideal target to develop antimicrobials for porcine bacterial pathogens. The three LuxS inhibitors identified in this study can be used as lead compounds for drug design.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Sun
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Song
authors.forename: Xinjuan
authors.initials: X
authors.lastname: Wu
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.forename: Ziduo
authors.initials: Z
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
mesh_terms: D016977:Actinobacillus pleuropneumoniae / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013437:Carbon-Sulfur Lyases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013437:Carbon-Sulfur Lyases; C117753:LuxS protein, Bacteria