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.

细菌细胞包膜是一种出色而复杂的结构，可从周围环境中守护细菌。革兰氏阴性细菌的一个定义特征是外膜（OM）的存在，该膜（OM）封装了这些生物的Pepperydoglycan层。虽然内膜（IM）由甘油磷脂（GPLS）组成，但OM是一个双层，具有极端的脂质不对称性，其GPL局限于内部叶片和脂多糖（LPS），而脂多糖（LPS）位于外部小叶中。这个独特的膜组织可为革兰氏阴性细菌提供保护大型极性分子以及亲脂性化合物，是对各种抗生素和有毒化合物的重要先天障碍。值得注意的是，高优先级阴性病原病原杆菌鲍曼尼（Baumannii）可能会完全使LPS生物合成作为对“最后度假”抗生素的耐药性的替代机制，称为多型多型polymyxins。该应用的主要目的是研究维持鲍曼尼a。Baumannii细胞包膜所需的机制，无论LPS状态如何。尽管不对称OM相对于GPL双层的益处显而易见，但由于其提供了不可渗透的障碍，但可以使用A. baumannii中的LPS重要性在存在或不存在LPS的情况下探索OM稳定性的新型机制。在AIM 1中，我们将研究细菌从LPS缺乏到LPS阳性细胞的过渡期间的变化，包括GPL转运如何影响LPS结构。对于目标2，我们的重点是鉴定支持LPS缺陷的基因，包括脂蛋白的作用以及如何将其转运到细胞表面，无论LPS状态如何。最后，在AIM 3中，我们将表征通过遗传和化学合成致死性筛查发现的LPS阳性A. Baumannii中OM稳定性所需的新型基因产品。鉴于当前的文献，该应用是建立在强大的科学前提的基础上，该前提解决了我们对鲍曼曼河细胞环境和其他革兰氏阴性病原体的理解时的主要差距。此外，该目标集中在高度组成的途径上，这些途径影响膜生物发生，细菌发病机理和抗菌发育。