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

• 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
• 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

 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环境条件下生存。革兰氏阴性菌经常改变其暴露于环境的外膜，即由内小叶甘油磷脂和基本外小叶脂寡糖（LPS）或脂多糖（LOS）组成的不对称双层。鲍曼不动杆菌是一种革兰氏阴性医院病原体，由于其能够对抗生素产生耐药性，因此在医疗保健环境中蓬勃发展。多药耐药A.鲍曼不动杆菌在过去的十年中已经变得广泛，并且靶向外膜中的基本LOS的最后一线抗生素如粘菌素已经越来越多地被处方用于治疗多药耐药性感染。而粘菌素耐药性是 这种情况曾经很罕见，但现在已不再是这种情况，特别是对于A。鲍曼不动杆菌。独特地，A.鲍曼不动杆菌可以完全关闭LOS的生物合成，从而产生对粘菌素和许多其它常用处方抗生素的抗性。这一发现是令人惊讶的，因为LPS/LOS通常对于革兰氏阴性细菌活力是必需的。导致LOS缺陷和由此产生的多药耐药表型的机制尚不清楚。该提案的总体目标是表征和理解一种新的多药耐药机制。该建议的具体目的是（i）了解LOS完全丧失的遗传要求和（ii）表征LOS缺陷型A中改变的外膜通透性屏障。鲍曼不动杆菌。这项工作的完成将有助于一个关键的知识体系LPS/LOS在革兰氏阴性菌的重要性，并提供一个新的多药耐药机制所需的分子机制的理解。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。