Citrate and Metal Efflux by IceT

IceT 的柠檬酸盐和金属流出

• 批准号: 8709707
• 负责人: Elaine R. Frawley
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709707
• 关键词: Alkaline Phosphatase; Amino Acids; Animals; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Proteins; Biological; Biological Assay; Biological Process; C-terminal; Cell membrane; Chemistry; Citrates; Complex; Coupled; Development; Electron Spin Resonance Spectroscopy; Enterobacteriaceae; Environment; Enzymes; Free Radicals; Galactosidase; Goals; Growth; Homologous Gene; Host Defense; Human; Hydrogen Peroxide; Immune system; In Vitro; Infection; Iron; Iron Overload; Knowledge; LacZ Genes; Mass Spectrum Analysis; Mediating; Metabolism; Metals; Modeling; Mus; Mutation; Nitric Oxide; Oxidation-Reduction; Paraquat; Peroxides; Plasma; Play; Predisposition; Production; Proteins; Pump; Regulation; Resistance; Role; Salmonella; Salmonella enterica; Stress; Structure-Activity Relationship; System; Vesicle; Virulence; catalyst; enteric pathogen; insight; interest; killings; member; mutant; novel therapeutics; pathogen; public health relevance; research study; response

DESCRIPTION (provided by applicant): Salmonella enterica serovar Typhimurium (S. Typhimurium) is a model enteric pathogen. Like many pathogens, S. Typhimurium requires iron for survival both in the environment and in the host. However, when host defenses damage iron containing bacterial proteins, intracellular free iron acts as a catalyst for production of free radicals. IceT is a stress-induced transporter in the major facilitator superfamily that is conserved throughout the Enterobacteriaceae. Its expression in S. Typhimurium leads to efflux of iron and citrate, which protects the bacteria from a variety of stresses and antibiotics. The goal of this proposal is to further characterize this intrinsic mechanism of bacterial stress resistance and understand its role in S. Typhimurium virulence. This will be accomplished by characterizing the specific substrates transported by IceT and elucidating the chemistry of transport, examining structure-function relationships in the IceT protein, and characterizing a homologue of IceT, YieO, that is also found in S. Typhimurium and may play a complementary role in intrinsic resistance to host defenses and antibiotics. Experiments will be conducted in vitro, in culture, and in a murine model of infection. These studies will provide insight into the function of two representative members of the major facilitator superfamily and the role regulation of bacterial metabolism plays in resistance to stress.

性状（由申请方提供）：鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌）是一种模式肠道病原体。与许多病原体一样，S.鼠伤寒需要铁在环境和宿主中生存。然而，当宿主防御破坏含铁的细菌蛋白质时，细胞内的游离铁充当自由基产生的催化剂。IceT是肠杆菌科中保守的主要易化超家族中的应激诱导转运蛋白。在S.鼠伤寒杆菌导致铁和柠檬酸盐的流出，从而保护细菌免受各种压力和抗生素的影响。本研究的目的是进一步阐明细菌抗逆的内在机制，并了解其在S。鼠伤寒毒力。这将通过表征由IceT转运的特异性底物和阐明转运的化学、检查IceT蛋白中的结构-功能关系以及表征IceT的同源物YieO（其也在S.鼠伤寒沙门氏菌和可能发挥互补作用的内在耐药性宿主防御和抗生素。实验将在体外、培养物和感染的鼠模型中进行。这些研究将深入了解主要促进剂超家族的两个代表性成员的功能以及细菌代谢调节在抵抗压力中的作用。