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Disarming Bacterial Virulence through Chemical Inhibition of the DNA Binding Domain of an AraC-like Transcriptional Activator Protein

机译:通过化学抑制AraC样转录激活蛋白的DNA结合域解除细菌致病力。

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摘要

The misuse of antibiotics during past decades has led to pervasive antibiotic resistance in bacteria. Hence, there is an urgent need for the development of new and alternative approaches to combat bacterial infections. In most bacterial pathogens the expression of virulence is tightly regulated at the transcriptional level. Therefore, targeting pathogens with drugs that interfere with virulence gene expression offers an effective alternative to conventional antimicrobial chemotherapy. Many Gram-negative intestinal pathogens produce AraC-like proteins that control the expression of genes required for infection. In this study we investigated the prototypical AraC-like virulence regulator, RegA, from the mouse attaching and effacing pathogen, Citrobacter rodentium, as a potential drug target. By screening a small molecule chemical library and chemical optimization, we identified two compounds that specifically inhibited the ability of RegA to activate its target promoters and thus reduced expression of a number of proteins required for virulence. Biophysical, biochemical, genetic, and computational analyses indicated that the more potent of these two compounds, which we named regacin, disrupts the DNA binding capacity of RegA by interacting with amino acid residues within a conserved region of the DNA binding domain. Oral administration of regacin to mice, commencing 15 min before or 12 h after oral inoculation with C. rodentium, caused highly significant attenuation of intestinal colonization by the mouse pathogen comparable to that of an isogenic regA-deletion mutant. These findings demonstrate that chemical inhibition of the DNA binding domains of transcriptional regulators is a viable strategy for the development of antimicrobial agents that target bacterial pathogens.
机译:在过去的几十年中,滥用抗生素已导致细菌普遍耐药。因此,迫切需要开发新的和替代的方法来对抗细菌感染。在大多数细菌病原体中,毒力的表达在转录水平上受到严格调节。因此,用干扰毒力基因表达的药物靶向病原体是常规抗微生物化疗的有效替代方法。许多革兰氏阴性肠道病原体会产生AraC样蛋白,从而控制感染所需基因的表达。在这项研究中,我们调查了小鼠附着和消灭病原体啮齿类柠檬酸杆菌作为潜在药物靶标的原型AraC样毒力调节剂RegA。通过筛选小分子化学文库和化学优化,我们鉴定了两种化合物,这些化合物特异性抑制RegA激活其靶标启动子的能力,从而减少了毒性所需的多种蛋白质的表达。生物物理,生化,遗传和计算分析表明,这两种化合物(我们称为regacin)的作用更强,它通过与DNA结合域保守区域内的氨基酸残基相互作用来破坏RegA的DNA结合能力。从口服啮齿类梭状芽胞杆菌口服疫苗开始或之前15分钟或口服后12小时开始,对小鼠进行瑞加辛口服给药,与同基因的regA缺失突变体相比,小鼠病原体的肠道定殖显着降低。这些发现表明,化学抑制转录调节子的DNA结合域是开发针对细菌病原体的抗微生物剂的可行策略。

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