Solving a Novel Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide

解决新的多药耐药性难题：脂寡糖的完全丧失

• 批准号: 8833481
• 负责人: Joseph Michael Boll
• 金额: $ 5.24万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833481
• 关键词: Acinetobacter baumannii; Anabolism; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Aptitude; Architecture; Bacteria; Bacterial Infections; Basic Science; Binding; Biological Assay; Blood; Cell Death; Cell Membrane Permeability; Cell Survival; Cells; Ciprofloxacin; Clinical; Colistin; Communities; Coupled; Cytolysis; Development; Drug resistance; Exposure to; Extravasation; Future; Genes; Genetic; Glycerophospholipids; Gram-Negative Bacteria; Healthcare; High-Throughput Nucleotide Sequencing; Infection; Knowledge; Laboratories; Lead; Life; Lipid A; Lipopolysaccharide Biosynthesis Pathway; Lipopolysaccharides; Medical; Membrane; Membrane Proteins; Molecular; Multi-Drug Resistance; Mutagenesis; Mutation; Nosocomial Infections; Nucleotides; Pathway interactions; Patients; Peptides; Permeability; Phenotype; Phospholipids; Pneumonia; Polymyxin Resistance; Polymyxins; Polysaccharides; Predisposition; Public Health; Resistance; Resistance development; Resort; Sequence Analysis; Surface; Surgical wound; Urinary tract infection; Vaccines; Variant; Work; antimicrobial; antimicrobial drug; capsule; clinically relevant; colistin resistance; genome sequencing; improved; inorganic phosphate; lipooligosaccharide; next generation sequencing; novel; novel therapeutics; pathogen; prevent; public health relevance; resistance gene; resistance mechanism; tigecycline

 DESCRIPTION (provided by applicant): Bacterial pathogens exploit various molecular mechanisms to survive unpredictable and adverse environmental conditions. Gram-negative bacteria often alter their environmentally exposed outer membrane, 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. Multidrg resistant A. baumannii have become widespread over the past decade and last-line antibiotics such as colistin, which target the essential lipooligosaccharide in the outer membrane, have been increasingly prescribed to treat multidrug resistant infections. While colistin resistance was once rare, this is no longer the case, especially regarding A. baumannii. Uniquely, A. baumannii can completely shut down lipopolysaccharide biosynthesis to develop resistance to colistin and many other commonly prescribed antibiotics. This finding is surprising because lipooligosaccharide and lipopolysaccharide were previously thought to be required for Gram-negative bacterial viability, but this multidrug resistance mechanism proves that it is not essential. Mechanisms 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 (i) to understand the genetic requirements for complete loss of lipooligosaccharide and (ii) to characterize the altered outer membrane permeability barrier after complete loss of lipooligosaccharide. Completion of this work will contribute an essential body of knowledge to the essentiality of lipooligosaccharide or lipopolysaccharide in Gram-negative bacteria and provide understanding of a molecular mechanism required for a novel multidrug resistance mechanism. The basic science framework from this proposal could also potentially lead to development of novel therapeutics and improved vaccines.

 描述（通过应用提供）：细菌病原体探索各种分子机制，以在不可预测和不利的环境条件下生存。革兰氏阴性细菌经常改变其环境暴露的外膜，一种不对称双层，由内部小叶甘油磷脂和必需的外部小叶lipoligosacacharide或 脂多糖。 ACINETOBACTER BAUMANNII是一种革兰氏阴性的医院病原体，在医疗保健环境中蓬勃发展，因为它具有对抗生素抗性的能力。在过去的十年中，抗多性抗体抗生素已越来越多，诸如colistin的最后一线抗生素（靶向外膜必需的脂糖糖糖）越来越多地处方以治疗抗多药物的抗性感染。而结肠蛋白的抗性是 一旦罕见，就不再是这种情况，尤其是关于鲍曼尼曲霉的。独特的是，鲍曼尼曲霉可以完全关闭脂多糖的生物合成，从而产生对结肠素和许多其他常规开处方的抗生素的抗性。这一发现令人惊讶，因为以前认为lipoligosacachicy和脂多糖是革兰氏阴性细菌的生存能力所必需的，但是这种多抗耐药机制证明了这不是必不可少的。尚不清楚导致这种多药抗性表型的机制，并且尚未探索治疗选择。该提案的总体目的是表征和理解一种新型的多药耐药机制。该提案的具体目的是（i）了解完全丧失脂糖糖酸和（ii）的遗传要求，以表征lipoligosacachide完全丢失后，外膜的外膜渗透性屏障的改变。这项工作的完成将为革兰氏阴性细菌中脂糖酸或脂多糖的本质提供重要的知识体系，并提供对新型多药耐药机制所需的分子机制的理解。该提案的基本科学框架也可能导致新的治疗和改善疫苗的发展。