The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii

多重耐药病原体鲍曼不动杆菌的细胞包膜

• 批准号: 10113527
• 负责人: Michael Stephen Trent
• 金额: $ 53.93万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-25 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10113527
• 关键词: Acinetobacter baumannii; Address; Amines; Anabolism; Antibiotic Resistance; Antibiotics; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Architecture; Bacteria; Bacterial Physiology; Biogenesis; Biology; Blood; Cell Maintenance; Cell Membrane Permeability; Cell surface; Cells; Cessation of life; Charge; Chemicals; Communicable Diseases; Complex; Core Assembly; Cytolysis; Data; Defect; Development; Disease; Encapsulated; Environment; Escherichia coli; Evolution; Extravasation; Genes; Genetic; Glycerophospholipids; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Growth; Human; Hydrophobicity; Hypersensitivity; Infection; Lipid A; Lipid Binding; Lipids; Lipopolysaccharide Biosynthesis Pathway; Lipopolysaccharides; Lipoproteins; Literature; Lung; Maintenance; Membrane; Membrane Lipids; Modification; Molecular; Multi-Drug Resistance; Nosocomial Infections; O Antigens; Oligosaccharides; Operative Surgical Procedures; Organism; Pathogenesis; Pathway interactions; Peptidoglycan; Phospholipases A; Poison; Polymyxin Resistance; Polymyxins; Process; Proteins; Resistance; Resort; Role; Series; Structure; Surface; System; Urinary tract infection; Virulence; World Health Organization; analog; antimicrobial; bacterial fitness; base; cell envelope; cell type; chemical genetics; drug resistant bacteria; emerging pathogen; experimental study; extensive drug resistance; fighting; fitness; gene product; inorganic phosphate; lipooligosaccharide; lipophilicity; membrane assembly; membrane biogenesis; multi-drug resistant pathogen; novel; novel therapeutics; null mutation; pathogen; prevent; priority pathogen; protein transport; resistance mechanism; response; sugar; tool; transposon sequencing; wound

The bacterial cell envelope is a remarkable and complex structure that guards bacteria from their surrounding environment. A defining feature of Gram-negative bacteria is the presence of an outer membrane (OM) that encapsulates the peptidoglycan layer of these organisms. While the inner membrane (IM) is composed of glycerophospholipids (GPLs), the OM is a bilayer with extreme lipid asymmetry with GPL confined to the inner leaflet and lipopolysaccharide (LPS) localized to the outer leaflet. This unique membrane organization affords Gram-negative bacteria protection from large polar molecules, as well as lipophilic compounds, serving as an essential innate barrier to a variety of antibiotics and toxic compounds. Remarkably, the high-priority Gram-negative pathogen Acinetobacter baumannii can completely inactivate LPS biosynthesis as an alternative mechanism of resistance to the “last-resort” antibiotics called polymyxins. The primary objective of this application is to investigate the mechanisms required for maintenance of the cell envelope of A. baumannii, regardless of LPS status. While the benefit of an asymmetric OM relative to a GPL bilayer is apparent due to the impermeable barrier it provides, the lack of LPS essentiality in A. baumannii can be used a tool to explore novel mechanisms of OM stability in both the presence or absence of LPS. In Aim 1, we will investigate changes to the bacterium during its transition from an LPS-deficient to a LPS-positive cell, including how GPL transport influences LPS structure. For Aim 2 our focus will be the identification of genes that support LPS-deficiency, including the role of lipoproteins and how they are transported to the cell surface regardless of LPS status. Finally, in Aim 3, we will characterize novel gene products necessary for OM stability in LPS-positive A. baumannii uncovered by a genetic and chemical synthetic lethality screen. Given the current literature, the application is built on a strong scientific premise addressing major gaps in our understanding of the A. baumannii cell envelope and other Gram-negative pathogens. Furthermore, the Aims focus on highly conserved pathways that impact membrane biogenesis, bacterial pathogenesis, and antimicrobial development.

细菌细胞膜是一种显着而复杂的结构，可以保护细菌免受周围环境的影响，其一个显着特征是存在包裹这些生物体肽聚糖层的外膜 (OM)。 IM) 由甘油磷脂 (GPL) 组成，OM 是具有极端脂质不对称性的双层，其中 GPL 局限于内叶，脂多糖 (LPS) 位于外叶。独特的膜组织为革兰氏阴性细菌提供保护，使其免受大极性分子和亲脂性化合物的侵害，作为多种抗生素和有毒化合物的重要先天屏障。值得注意的是，高优先级革兰氏阴性病原体鲍曼不动杆菌可以完全失活。 LPS 生物合成作为对多粘菌素“最后手段”抗生素耐药的替代机制 该应用的主要目的是研究维持细胞包膜所需的机制。鲍曼不动杆菌，无论 LPS 状态如何，虽然由于其提供的不可渗透的屏障，不对称 OM 相对于 GPL 双层的好处是显而易见的，但鲍曼不动杆菌中缺乏 LPS 的必要性可以用作探索新机制的工具。在存在或不存在 LPS 的情况下 OM 稳定性 在目标 1 中，我们将研究细菌从 LPS 缺陷细胞转变为 LPS 阳性细胞期间的变化，包括 GPL 如何转运。对于目标 2，我们的重点是识别支持 ​​LPS 缺乏的基因，包括脂蛋白的作用以及它们如何转运到细胞表面，无论 LPS 状态如何。最后，在目标 3 中，我们将描述新的特征。通过遗传和化学合成致死率筛选发现的 LPS 阳性鲍曼不动杆菌中 OM 稳定性所必需的基因产物 鉴于当前的文献，该应用建立在强有力的科学前提之上，解决了我们对鲍曼不动杆菌理解中的主要差距。此外，该目标重点关注影响膜生物发生、细菌发病机制和抗菌药物发展的高度保守途径。