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（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。革兰氏阴性细菌通常会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lipligosacacharide（LPS）或脂多糖（LOS）组成。 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，抗多药抗生素已成为宽度，诸如colistin的最后一线抗生素（靶向外膜基本LOS）已被越来越多地处方以治疗耐多药感染。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LOS生物合成，以发展对Colistin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LPS/LOS通常对于革兰氏阴性细菌的生存能力至关重要。尚不清楚导致LOS缺乏症和由此产生的多药耐药表型的机制。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）了解完全丢失LOS的遗传要求，以及（ii）表征LOS缺乏的A. Baumannii中膜外膜渗透性屏障的改变。这项工作的完成将为LPS/LOS在革兰氏阴性细菌中的重要性提供重要的知识，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。