Solving a Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide

解决多药耐药性难题：脂寡糖完全丧失

• 批准号: 9808273
• 负责人: Joseph Michael Boll
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808273
• 关键词: Acinetobacter baumannii; Affinity; Anabolism; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Cationic Peptides; Basic Science; Binding; Bypass; Cell surface; Cells; Cellular Structures; Charge; Clinical; Colistin; Data; Development; Drug Design; Exposure to; Future; Genes; Genetic Determinism; Genetic Screening; Genetic Transcription; Glycerophospholipids; Goals; Gram-Negative Bacteria; Infection; Intelligence; Knowledge; Lead; Left; Lipid A; Lipid Bilayers; Lipopolysaccharides; Lipoproteins; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Analysis; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mutation; Pathway interactions; Peptidoglycan; Peptidyltransferase; Permeability; Phenotype; Polymyxins; Proteins; Public Health; Research; Resistance; Resistance development; Role; Signal Transduction; Surface; System; Treatment Failure; Vaccines; antimicrobial; cell envelope; clinically significant; colistin resistance; health care settings; improved; lipooligosaccharide; mutant; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; periplasm; resistance mechanism

Project Summary/Abstract Bacterial pathogens exploit various molecular mechanisms to survive adverse environmental conditions. Gram-negative bacteria modify their outer membrane, which is an asymmetric bilayer consisting of inner leaflet glycerophospholipids and essential outer leaflet lipooligosaccharide or lipopolysaccharide. Acinetobacter baumannii is a Gram-negative nosocomial pathogen that thrives in healthcare settings because of its ability to develop resistance to antibiotics. Multidrug resistant A. baumannii have become widespread over the past decade and last-line antibiotics such as colistin, which targets the lipid A domain of lipooligosaccharide in the outer membrane, has been increasingly prescribed to treat infections. While colistin resistance was once rare, A. baumannii has developed a unique resistance mechanism. A. baumannii can completely shut down lipid A biosynthesis to develop multidrug resistance to many prescribed antibiotics, including colistin. This finding is surprising because lipopolysaccharide was thought to be required for Gram-negative viability, but this mechanism proves otherwise. Molecular factors that contribute to this multidrug resistance phenotype are not understood and treatment options have not been explored. The overall objective of this proposal is to characterize and understand a novel multidrug resistance mechanism. The Specific Aims of this proposal are to (i) Characterize the outer membrane proteins that support LOS- A. baumannii survival and (ii) characterization of the BaeSR two-component system and its regulatory products. Completion of these AIMS will advance our body of knowledge to understand the essentiality of lipid A in Gram-negative bacteria and provide understanding of a molecular mechanism required for a novel multidrug resistance mechanism. Furthermore, the findings from this proposal could also potentially lead to development of novel therapeutics and improved vaccines.

项目摘要/摘要 细菌病原体利用各种分子机制在不利的环境条件下生存。 革兰氏阴性细菌修饰其外膜，这是一个不对称双层，由内部小叶组成 甘油磷脂和必需的外部小叶脂肪糖或脂多糖。扫视杆菌 鲍曼尼（Baumannii 发展抗生素的抗性。抗多药的A. Baumannii在过去变得广泛 十年和最后一线抗生素，例如colistin，它靶向脂质的脂肪含糖领域 外膜，已越来越多地处方以治疗感染。虽然抗colistin的耐药性曾经是罕见的，但 A.鲍曼尼（A. Baumannii）开发了一种独特的抗性机制。 A. Baumannii可以完全关闭脂质A 生物合成以对包括大肠菌素在内的许多处方抗生素产生多药耐药性。这个发现是 令人惊讶的是，革兰氏阴性的生存能力被认为需要脂多糖，但是 机制证明否则。有助于这种多药抗性表型的分子因子不是 理解和治疗方案尚未探索。 该提案的总体目的是表征和理解一种新型的多药电阻 机制。该建议的具体目的是（i）表征外膜蛋白 支持Los-A。Baumannii生存和（ii）Baesr两组分系统及其表征 监管产品。这些目标的完成将促进我们的知识体系，以了解 脂质A在革兰氏阴性细菌中的重要性，并提供对所需分子机制的理解 用于一种新型的多药电阻机制。此外，该提案的发现也可能有可能 导致新型治疗剂和改善疫苗的发展。