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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Small-molecule inhibitors of the pseudaminic acid biosynthetic pathway: Targeting motility as a key bacterial virulence factor
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Small-molecule inhibitors of the pseudaminic acid biosynthetic pathway: Targeting motility as a key bacterial virulence factor

机译：伪酸生物合成途径的小分子抑制剂：靶向运动作为关键细菌毒力因子

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摘要

Helicobacter pylori is motile by means of polar flagella, and this motility has been shown to play a critical role in pathogenicity. The major structural flagellin proteins have been shown to be glycosylated with the nonulosonate sugar, pseudaminic acid (Pse). This glycan is unique to microorganisms, and the process of flagellin glycosylation is required for H. pylori flagellar assembly and consequent motility. As such, the Pse biosynthetic pathway offers considerable potential as an antivirulence drug target, especially since motility is required for H. pylori colonization and persistence in the host. This report describes screening the five Pse biosynthetic enzymes for small-molecule inhibitors using both high-throughput screening (HTS) and in silico (virtual screening [VS]) approaches. Using a 100,000-compound library, 1,773 hits that exhibited a 40% threshold inhibition at a 10 μM concentration were identified by HTS. In addition, VS efforts using a 1.6-million compound library directed at two pathway enzymes identified 80 hits, 4 of which exhibited reasonable inhibition at a 10 μM concentration in vitro. Further secondary screening which identified 320 unique molecular structures or validated hits was performed. Following kinetic studies and structureactivity relationship (SAR) analysis of selected inhibitors from our refined list of 320 compounds, we demonstrated that three inhibitors with 50% inhibitory concentrations (IC50s) of approximately 14 μM, which belonged to a distinct chemical cluster, were able to penetrate the Gram-negative cell membrane and prevent formation of flagella.
机译：幽门螺杆菌通过极生鞭毛运动，这种运动已被证明在致病性中起关键作用。已显示主要的鞭毛蛋白结构蛋白已被非超声糖，伪氨基酸（Pseudaminic acid，Pse）糖基化。这种聚糖是微生物独有的，鞭毛蛋白糖基化的过程是幽门螺杆菌鞭毛组装和随之而来的运动所必需的。因此，Pse生物合成途径具有作为抗毒药物靶标的巨大潜力，特别是因为幽门螺杆菌的定殖和在宿主中的持久性需要运动性。本报告介绍了使用高通量筛选（HTS）和计算机模拟（虚拟筛选[VS]）方法筛选5种Pse生物合成酶的小分子抑制剂。使用100,000种化合物的文库，通过HTS鉴定了1,773个命中物，在10μM浓度下表现出40％的阈值抑制作用。此外，使用160万个针对两种途径酶的化合物库进行的VS研究确定了80个命中，其中4个在体外以10μM的浓度表现出合理的抑制作用。进行了进一步的二次筛选，确定了320个独特的分子结构或经过验证的命中。经过动力学研究和从我们精选的320种化合物中选择的抑制剂的结构活性关系（SAR）分析，我们证明了三种抑制剂的50％抑制浓度（IC50）约为14μM，它们属于不同的化学簇，它们能够穿透革兰氏阴性细胞膜并防止鞭毛形成。

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