Structural and functional studies of YbtPQ for fighting bacterial infections

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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.