Reinforcing the barrier: Understanding how cell envelope modifications promote intrinsic antimicrobial tolerance and resistance in Acinetobacter baumannii

强化屏障：了解细胞包膜修饰如何促进鲍曼不动杆菌内在的抗菌药物耐受性和耐药性

• 批准号: 10437019
• 负责人: Joseph Michael Boll
• 金额: $ 36.66万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437019
• 关键词: Acinetobacter baumannii; Address; Antibiotic Resistance; Antimicrobial Resistance; Bacteremia; Cell Wall; Colistin; Defect; Development; Enzymes; Fostering; Gram-Negative Bacteria; Hospitals; Human; Infection; Intrinsic factor; Knowledge; Lead; Link; Membrane; Mission; Modeling; Modification; Multi-Drug Resistance; Nosocomial Infections; Peptidoglycan; Pharmaceutical Preparations; Phenotype; Public Health; Regimen; Resistance; Resort; Stress; Superbug; Therapeutic; Treatment Protocols; United States National Institutes of Health; Urinary tract; Work; Wound Infection; antimicrobial; antimicrobial tolerance; carbapenem resistance; cell envelope; colistin resistance; combat; combinatorial; design; extensive drug resistance; human disease; improved; membrane assembly; pathogen; resistance gene; resistance mechanism; response

Project Summary/Abstract Emergence of multidrug and extensively drug resistant Gram-negative bacteria is a growing problem that threatens established antimicrobial treatment protocols. Acinetobacter baumannii is an emerging critical threat pathogen notorious for its ability to rapidly develop intrinsic multidrug resistance. A. baumannii causes hospital-acquired infections, which manifest as bacteremia, urinary tract and wound infections. In the US, an estimated 60% of hospital-acquired A. baumannii infections were multidrug resistant, often including carbapenem resistance, which leaves colistin as the “last-resort” treatment option. However, colistin resistance has also emerged. There is an urgent need to understand intrinsic mechanisms that promote antibiotic resistance phenotypes in A. baumannii to guide alternative antimicrobial strategies. Our preliminary work has identified factors that promote acquisition of multidrug resistance, including carbapenem and colistin resistance, in A. baumannii. Specifically, links between the outer membrane and peptidoglycan layers of the cell envelope are key for the resistance phenotypes, where one layer compensates for defects in the other. While enzymes that assemble the outer membrane and cell wall are largely known, A. baumannii encodes unique regulatory mechanisms to control their activity in response to stress. In this proposal, we will address three important questions to understand intrinsic antibiotic resistance in A. baumannii. The questions will explore the relationship between peptidoglycan and outer membrane assembly, which is poorly understood in Gram-negative bacteria. Findings from this work will enable us to build a model of intrinsic factors in A. baumannii that lead to multidrug resistance and will help in the design of combinatorial drug regimens that target both essential layers, thus precluding resistance; consequently, our findings support the National Institute of Health mission, which aims to foster fundamental discoveries to reduce human disease.

项目概要/摘要 多重耐药和广泛耐药革兰氏阴性菌的出现是一个日益严重的问题，威胁着 已制定的抗菌治疗方案。鲍曼不动杆菌是一种新兴的严重威胁病原体。 鲍曼不动杆菌因其快速产生内在多重耐药性而臭名昭著，可导致医院获得性耐药。 在美国，估计有 60% 的感染表现为菌血症、尿路感染和伤口感染。 医院获得性鲍曼不动杆菌感染具有多重耐药性，通常包括碳青霉烯类耐药性，这 将粘菌素作为“最后手段”的治疗选择 然而，粘菌素耐药性也出现了。 迫切需要了解促进鲍曼不动杆菌抗生素耐药表型的内在机制 指导替代抗菌策略。我们的初步工作已经确定了促进获得抗菌药物的因素。 具体而言，鲍曼不动杆菌中的多药耐药性，包括碳青霉烯类和粘菌素耐药性之间的联系。 细胞膜的外膜和肽聚糖层是耐药表型的关键，其中之一 一层弥补了另一层的缺陷，而组装外膜和细胞壁的酶则是。 众所周知，鲍曼不动杆菌编码独特的调节机制来控制其响应压力的活动。 在本提案中，我们将解决三个重要问题，以了解A. 固有的抗生素耐药性。 这些问题将探讨肽聚糖和外膜组装之间的关系。 我们对革兰氏阴性细菌知之甚少，这项工作的发现将使我们能够建立一个内在的模型。 鲍曼不动杆菌中导致多重耐药性的因素将有助于设计组合药物方案 针对两个基本层，从而排除阻力；因此，我们的研究结果支持国家党； 健康研究所的使命，旨在促进减少人类疾病的基本发现。