State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, 430070, China.
Curr Microbiol. 2013 Nov;67(5):564-71. doi: 10.1007/s00284-013-0403-9. Epub 2013 Jun 7.
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.
LuxS 是一种参与激活甲基循环的保守细菌酶，催化 S- 核糖同型半胱氨酸（SRH）生成半胱氨酸和 AI-2（种间群体感应信号分子）。该酶已被报道对胸膜肺炎放线杆菌在其自然宿主中的存活至关重要。因此，它是一种针对胸膜肺炎放线杆菌的潜在药物靶点，胸膜肺炎放线杆菌是一种重要的猪呼吸道病原体，在全球范围内给养猪业造成了巨大的经济损失。在本研究中，使用胸膜肺炎放线杆菌的重组 LuxS 建立了酶活性测定方法。通过软件 vROCS 从 Specs 化合物库中筛选出 35 种与 SRH 形状相似的化合物，并对 LuxS 抑制作用进行评估。有三种化合物可以抑制 LuxS 活性。其中两种被确认为竞争性抑制剂，第三种为非竞争性抑制剂。这三种化合物均对胸膜肺炎放线杆菌和其他两种重要的猪病原体副猪嗜血杆菌和猪链球菌的生长表现出抑制作用，MIC50 值范围为 11 至 51μg/ml。在对细菌生长有抑制作用的浓度下，这些化合物对猪 PK-15 细胞没有明显的细胞毒性作用。这些结果表明 LuxS 是开发猪细菌病原体抗菌药物的理想靶点。本研究中鉴定的三种 LuxS 抑制剂可作为药物设计的先导化合物。
