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首页> 外文期刊>Journal of Medical Microbiology: An Official Journal of the Pathological Society of Great Britain and Ireland >An antipathogenic compound that targets the OxyR peroxide sensor in Pseudomonas aeruginosa
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An antipathogenic compound that targets the OxyR peroxide sensor in Pseudomonas aeruginosa

机译：靶向<斜体>假单胞菌铜绿假单胞菌（Aeruginosa）靶向oxyr过氧化物传感器的抗体致原性化合物

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Introduction Antipathogenic or antivirulence strategy is to target a virulence pathway that is dispensable for growth, in the hope to mitigate the selection for drug resistance. Hypothesis/Gap Statment Peroxide stress responses are one of the conserved virulence pathways in bacterial pathogens and thus good targets for antipathogenic strategy. Aim This study aims to identify a new chemical compound that targets OxyR, the peroxide sensor required for the full virulence of the opportunistic human pathogen, Pseudomonas aeruginosa . Methodology Computer-based virtual screening under consideration of the ‘eNTRy’ rules and molecular docking were conducted on the reduced form of the OxyR regulatory domain (RD). Selected hits were validated by their ability to phenocopy the oxyR null mutant and modulate the redox cycle of OxyR. Results We first isolated three robust chemical hits that inhibit OxyR without affecting prototrophic growth or viability. One (compound 1) of those affected the redox cycle of OxyR in response to H _(2)O _(2) treatment, in a way to impair its function. Compound 1 displayed selective antibacterial efficacy against P. aeruginosa in Drosophila infection model, without antibacterial activity against Staphylococcus aureus . Conclusion These results suggest that compound 1 could be an antipathogenic hit inhibiting the P. aeruginosa OxyR. More importantly, our study provides an insight into the computer-based discovery of new-paradigm selective antibacterials to treat Gram-negative bacterial infections presumably with few concerns of drug resistance.
机译：简介抗病原菌或antivirulence战略是针对一个致病途径是可有可无的成长，希望减轻耐药性的选择。假设/ GAP Statment过氧化应激反应是在细菌病原体的毒力保守的途径，从而很好的目标抗病原体策略之一。目的这项研究的目的是确定新的化学化合物的目标OxyR，为人类机会致病菌，铜绿假单胞菌的全毒力所需要的过氧化氢传感器。所考虑的“条目”规则和分子对接基于计算机的方法的虚拟筛选中的OxyR调节结构域（RD）的还原形式上进行的。选择命中通过其表型模拟的oxyR无效突变体和调节OxyR的氧化还原循环能力验证。结果我们首先分离出抑制OxyR不影响原养型生长或存活3次健壮化学命中。其中的一个（化合物1）的影响OxyR的氧化还原循环响应至H _（2）O _（2）治疗，在某种程度上损害其功能。化合物1显示针对果蝇感染模型绿脓杆菌选择性抗菌效力，而不对金黄色葡萄球菌的抗菌活性。结论这些结果表明，化合物1可以是抗病原体的命中抑制铜绿假单胞菌OxyR。更重要的是，我们的研究提供了洞察的新范式选择抗菌药物的基于计算机的发现与耐药性有些担心想必治疗革兰氏阴性细菌感染。

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