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.

项目概要/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。 革兰氏阴性细菌改变其外膜，这是一个由内部小叶组成的不对称双层 甘油磷脂和必需的外叶脂寡糖或脂多糖。不动杆菌属 鲍曼不动杆菌是一种革兰氏阴性医院病原体，在医疗保健环境中大量繁殖，因为它能够 产生对抗生素的耐药性。多重耐药鲍曼不动杆菌在过去已经广泛传播 十年和最后一线抗生素，如粘菌素，其目标是脂寡糖的脂质 A 结构域 外膜已越来越多地用于治疗感染。虽然粘菌素耐药性曾经很少见， 鲍曼不动杆菌形成了独特的耐药机制。鲍曼不动杆菌可以完全关闭脂质A 生物合成以产生对许多处方抗生素（包括粘菌素）的多重耐药性。这一发现是 令人惊讶的是，脂多糖被认为是革兰氏阴性菌生存所必需的，但这 机制证明并非如此。导致这种多药耐药表型的分子因素不是 尚未了解并探索治疗方案。 该提案的总体目标是表征和理解新型多药耐药性 机制。该提案的具体目标是 (i) 表征外膜蛋白 支持 LOS- 鲍曼不动杆菌的存活和 (ii) BaeSR 双组分系统及其表征 监管产品。完成这些目标将提高我们的知识体系，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 寻找一种新的多重耐药机制。此外，该提案的调查结果还可能 导致新疗法和改进疫苗的开发。