Function of novel antibacterial toxins

新型抗菌毒素的作用

• 批准号: 10656167
• 负责人: Celia Goulding
• 金额: $ 31.25万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656167
• 关键词: Acids; Active Sites; Acyl Carrier Protein; Acylation; Acyltransferase; Amino Acid Sequence; Anti-Bacterial Agents; Bacteria; Bacterial Genome; Bacterial Toxins; Binding; Biochemical; C-terminal; Calorimetry; Cell surface; Cells; Chimera organism; Citrobacter rodentium; Communication; Complex; Crystallization; Crystallography; Cysteine; Cytoplasm; Data; Deaminase; Ecology; Escherichia coli; Evolution; Family; Gammaproteobacteria; Genetic; Goals; Gram-Negative Bacteria; Growth; Immunity; In Vitro; Length; Lipopolysaccharides; Lysine; Mediating; Membrane; Membrane Proteins; Modification; Molecular; Molecular Genetics; Molecular Target; Pathway interactions; Peptide Hydrolases; Peptides; Predisposition; Protein Secretion; Proteins; Providencia; Publishing; Reaction; Research; Resolution; Ribonucleases; Series; Site; Structure; Substrate Specificity; Surveys; System; Testing; Toxin; Transfer RNA; Variant; Yersinia; antimicrobial; biophysical analysis; biophysical techniques; cell killing; functional plasticity; genetic approach; human pathogen; insight; novel; novel strategies; pathogen; pathogenic bacteria; protein complex; protein protein interaction; receptor; receptor binding; reconstitution

Project summary Bacteria have evolved complex strategies to compete and communicate with one another. One important mechanism of inter-bacterial competition is contact-dependent growth inhibition (CDI). CDI systems are found in a wide variety of Gram-negative bacteria, including many important human pathogens. CDI is mediated by the CdiB/CdiA family of two-partner secretion proteins. CdiB is an Omp85 outer-membrane protein that is required for the export and assembly of the CdiA exoprotein onto the cell surface. CdiA binds to receptors on susceptible bacteria and then delivers its C-terminal toxin domain (CdiA-CT) into the target cell. These systems also encode CdiI immunity proteins, which specifically bind to the CdiA-CT and neutralize toxin activity to protect CDI+ cells from auto-inhibition. CdiA-CT/CdiI sequences are highly variable, with >130 distinct toxin/immunity protein sequence types recognized in bacterial genomes. CdiA-CT toxins are modular and can be exchanged between CdiA proteins to generate functional chimeras. These observations indicate that many different kinds of toxic cargo can be delivered into the cytoplasm of target bacteria. This application seeks to determine the molecular and structural underpinnings that enable this remarkable functional plasticity. We will use a combination of genetic, biochemical and biophysical approaches to gain mechanistic insight into the network of protein-protein interactions that govern CDI. This research will significantly increase our understanding of the ecology and evolution of bacterial pathogens and could inform novel strategies for antimicrobial therapy.

项目概要 细菌已经进化出复杂的策略来相互竞争和交流。一 细菌间竞争的重要机制是接触依赖性生长抑制（CDI）。 CDI系统 存在于多种革兰氏阴性细菌中，包括许多重要的人类病原体。 CDI 是 由二伙伴分泌蛋白的 CdiB/CdiA 家族介导。 CdiB 是 Omp85 外膜 CdiA 外蛋白输出和组装到细胞表面所需的蛋白质。 CdiA 结合 敏感细菌上的受体，然后将其 C 端毒素结构域 (CdiA-CT) 传递到靶细胞中。 这些系统还编码 CdiI 免疫蛋白，该蛋白特异性结合 CdiA-CT 并中和毒素 保护 CDI+ 细胞免受自身抑制的活性。 CdiA-CT/CdiI 序列高度可变，>130 细菌基因组中识别出的不同毒素/免疫蛋白序列类型。 CdiA-CT 毒素是模块化的 并且可以在 CdiA 蛋白之间交换以产生功能性嵌合体。这些观察表明 许多不同种类的有毒物质可以被输送到目标细菌的细胞质中。这个应用程序 试图确定实现这种非凡功能可塑性的分子和结构基础。 我们将结合遗传、生物化学和生物物理方法来深入了解 控制 CDI 的蛋白质-蛋白质相互作用网络。这项研究将显着提高我们的 了解细菌病原体的生态和进化，并可以为细菌病原体的新策略提供信息 抗菌治疗。