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首页> 外文期刊>Acta crystallographica, Section F. Structural biology and crystallization communications >The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery
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The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery

机译：针对铜绿假单胞菌的AEROPATH项目：结晶学研究，用于评估早期药物发现中的潜在靶标

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摘要

Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.
机译：由于抗生素耐药性的传播，细菌感染越来越难以治疗。人们最关注的是革兰氏阴性细菌，对于这些细菌而言，新抗菌药物的发现尤为稀少。为了加快药物发现的早期步骤，由欧盟资助的AEROPATH项目旨在通过应用多学科方法，包括靶标验证，结构表征，分析开发和从小分子文库中进行命中鉴定，来确定机会性病原体铜绿假单胞菌中的新靶标。 。在这里，描述了用于靶标选择的策略，并报道了蛋白质生产和结构分析的进展。在102个选定的靶标中，有84个可以可溶性形式生产，并且已经确定了39种蛋白质的从头结构。此处报道了八个靶标的晶体结构，范围从假设的未知蛋白到不同功能类别（PA1645，PA1648，PA2169，PA3770，PA4098，PA4485，PA4992和PA5259）的代谢酶。结构信息有望为改进基于片段和高通量筛选活动中鉴定的命中化合物提供坚实的基础。

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