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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：
9102680
负责人：
Michael Stephen Trent
金额：
$ 22.5万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102680
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 Extreme drug resistant tuberculosis 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 Outcome 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 genome sequencing improved inorganic phosphate lipooligosaccharide loss of function mutation monolayer novel novel therapeutics pathogen prevent resistance gene resistance mechanism tigecycline transcriptome sequencing

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.