Rethinking the barrier: How a Gram-negative bacterium alters its surface to become multidrug resistant

重新思考屏障：革兰氏阴性细菌如何改变其表面以产生多重耐药性

基本信息

批准号：
9090098
负责人：
Michael Stephen Trent
金额：
$ 18.75万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9090098
关键词：
Acinetobacter baumannii Anabolism Antibiotic Resistance Antibiotics Architecture Bacteria Basic Science Binding Biochemical Blood Cell Membrane Permeability Cell Survival Cells Cessation of life Ciprofloxacin Clinical Colistin Complex Cytolysis Development Drug resistance Exposure to Extravasation Future Genes Genetic Glycerophospholipids Gram-Negative Bacteria Health Healthcare High-Throughput Nucleotide Sequencing Infection Knowledge Laboratories Lead Life Lipid A Lipopolysaccharide Biosynthesis Pathway Lipopolysaccharides Lung Medical Membrane Methods Molecular Molecular Target Multi-Drug Resistance Mutagenesis Mutation Nosocomial Infections Patient-Focused Outcomes Patients Permeability Phenotype Phospholipids Polymyxins Property Proteomics Protocols documentation Public Health Resistance Resistance development Resort Structure Surface Surgical wound Urinary tract infection Vaccines Work antimicrobial base clinically relevant colistin resistance effective therapy extensive drug resistance genome sequencing improved inorganic phosphate lipooligosaccharide loss of function mutation monolayer novel novel therapeutics pathogen prevent resistance gene resistance mechanism tigecycline transcriptome sequencing whole genome

项目摘要

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 (LPS) or lipopolysaccharide (LOS). 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 target the essential LOS 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 shutdown LOS biosynthesis to develop resistance to colistin and many other commonly prescribed antibiotics. This finding is surprising since LPS/LOS are typically essential for Gram-negative bacterial viability. Mechanisms that contribute to LOS deficiency and the resulting multidrug resistance phenotype are not understood. 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 LOS and (ii) to characterize the altered outer membrane permeability barrier in LOS deficient A. baumannii. Completion of this work will contribute a critical body of knowledge to the essentiality of LPS/LOS in Gram-negative bacteria and provide understanding of the molecular mechanisms 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（由申请人提供）：细菌病原体利用各种分子机制在不可预测的不利细菌环境条件下生存，革兰氏阴性细菌经常改变其暴露于环境的外膜，即由内叶甘油磷脂和必需的外叶脂寡糖（LPS）或组成的不对称双层。脂多糖 (LOS) 是一种革兰氏阴性医院病原体，因其能力而在医疗机构中大量繁殖。过去十年中，多药耐药鲍曼不动杆菌已变得普遍，而最后一线抗生素（例如针对外膜中必需的 LOS）已越来越多地用于治疗多药耐药感染。曾是鲍曼不动杆菌曾经很少见，但现在情况已不再如此，特别是鲍曼不动杆菌可以完全关闭 LOS 生物合成，从而产生对粘菌素和许多其他常用抗生素的耐药性，因为 LPS/LOS 通常对于细菌合成至关重要。导致 LOS 缺乏和由此产生的多药耐药表型的革兰氏阴性细菌活力的机制尚不清楚。该提案的总体目标是表征和了解一种新的多药耐药机制。该提案的目的是 (i) 了解 LOS 完全丧失的遗传要求，以及 (ii) 描述 LOS 缺陷的鲍曼不动杆菌外膜渗透性屏障的改变。这项工作的完成将为该领域贡献重要的知识体系。该提案的基础科学框架也可能导致新疗法和改进疫苗的开发。