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: 10542396
• 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/10542396
• 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; Pharmaceutical Preparations; Phospholipases A; Poison; Polymyxin Resistance; Polymyxins; Process; Proteins; Resistance; Role; Series; Structure; Surface; System; Urinary tract infection; Virulence; World Health Organization; analog; antimicrobial; bacterial fitness; cell envelope; cell type; 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.

细菌细胞被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。革兰氏阴性菌的一个定义特征是存在包封这些生物体的肽聚糖层的外膜（OM）。虽然内膜（IM）由甘油磷脂（GPL）组成，但OM是具有极端脂质不对称性的双层，GPL局限于内瓣叶，脂多糖（LPS）局限于外瓣叶。这种独特的膜组织为革兰氏阴性菌提供了保护，使其免受大极性分子以及亲脂性化合物的侵害，作为各种抗生素和有毒化合物的基本先天屏障。 值得注意的是，高优先级革兰氏阴性病原体鲍氏不动杆菌可以完全抑制LPS生物合成，作为对称为多粘菌素的“最后手段”抗生素的抗性的替代机制。本申请的主要目的是研究维持A.鲍曼不动杆菌，无论LPS状态如何。虽然不对称OM相对于GPL双层的益处是明显的，因为它提供了不可渗透的屏障，但A.鲍曼不动杆菌可用于探索在存在或不存在LPS的情况下OM稳定性的新机制。在目标1中，我们将研究细菌从LPS缺陷细胞向LPS阳性细胞转变过程中的变化，包括GPL转运如何影响LPS结构。对于目标2，我们的重点将是识别支持LPS缺乏的基因，包括脂蛋白的作用以及它们如何被转运到细胞表面，而不管LPS状态如何。最后，在目标3中，我们将表征LPS阳性A中OM稳定性所必需的新基因产物。通过基因和化学合成致死筛选发现的鲍曼不动杆菌。鉴于目前的文献，该应用程序是建立在一个强大的科学前提解决我们对A的理解的主要差距。鲍曼不动杆菌细胞包膜和其它革兰氏阴性病原体。此外，目标集中于影响膜生物发生、细菌发病机理和抗菌剂开发的高度保守的途径。