Structural and functional studies of YbtPQ for fighting bacterial infections

寄主和病原体之间永恒的战争之一是争夺营养金属离子。细菌有 进化出了多种途径来实现这一点，包括由一组名为 通常对细菌的毒力至关重要的铁载体。长期目标是帮助开发潜力 靶向铁载体介导的金属摄取过程的分子，从而治疗细菌感染。然而， 在这一过程中的关键步骤之一是由三磷酸腺苷结合盒(ABC)进口体介导的底物摄取。 人们对此知之甚少。这项建议的总体目标是通过研究详细的 尿路致病性大肠埃希氏菌(UPEC)特异的铁载体ABC导入子的分子机制 Yersiniabactin(Ybt)进口商YbtPQ。理由是，在这里获得了详细的知识，这将是可能的 设计和优化专门针对YbtPQ的小分子。为了实现这一目标，有两个具体目标 将继续：1)通过结构研究重建其完整的运输循环；以及2)调查其 底物选择性和与潜在抑制剂的相互作用。这里使用的多学科方法包括 结构生物学、生物化学、生物物理学以及微生物学。该提议具有创新性，因为1) YbtPQ是一个类似出口商的进口商，代表着与ABC的既定范式的重大背离 2)结果将提供潜在的YbtPQ抑制剂，可能在临床上有用 未来。最后但并非最不重要的一点是，这项研究也具有重要意义，因为它不仅有望揭示新的分子 出口商类进口商的机制，也为药品的进一步发展提供了科学依据 针对铁载体ABC进口商。

One of the eternal wars between the host and pathogens is the fight for nutritional metal ions. Bacteria have evolved multiple pathways to achieve that, including the one mediated by a group of small molecules called siderophores that are often critical for the virulence of the bacteria. The long-term goal is to help develop potential molecules targeting the siderophore-mediated metal uptake process, so to treat bacterial infections. However, one of the critical steps in this process, the substrate uptake mediated by ATP-binding-cassette (ABC) importers, is poorly understood. The overall objective in this proposal is to address the problem by studying the detailed molecular mechanism of a specific siderophore ABC importer from uropathogenic Escherichia coli (UPEC): the yersiniabactin (Ybt) importer YbtPQ. The rational is that, with detailed knowledge gained here, it will be possible to design and optimize small molecules to specifically target YbtPQ. To accomplish the goal, two specific aims will be pursued: 1) reconstructing its complete transport cycle by structural studies; and 2) investigating its substrate selectivity and interaction with potential inhibitors. The multidisciplinary approach used here include structural biology, biochemistry, biophysics, as well as microbiology. The proposal is innovative because 1) YbtPQ is an exporter-like importer, representing a substantial departure from the established paradigm of ABC importers; and 2) the results will provide potential inhibitors against YbtPQ that could be clinically useful in the future. Last but not least, this study is also significant because it is expected to not only reveal novel molecular mechanism of exporter-like importer, but also provide scientific justification for further development of drugs against siderophore ABC importers.