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

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 制定了抗菌治疗方案。鲍曼不动杆菌是一种新兴的严重威胁病原体 它因其迅速发展内在多药耐药性的能力而臭名昭著。A.鲍曼不动杆菌引起医院获得性 感染，表现为菌血症、尿路和伤口感染。在美国，估计有60%的 医院获得性A.鲍曼不动杆菌感染具有多药耐药性，通常包括碳青霉烯类耐药， 使得粘菌素成为“最后的”治疗选择。然而，也出现了粘菌素耐药性。有一个 迫切需要了解的内在机制，促进抗生素耐药表型在A。鲍曼不动杆菌对 指导替代抗菌策略。我们的初步工作已经确定了促进收购的因素， 多药耐药，包括碳青霉烯类和粘菌素耐药。鲍曼不动杆菌。具体而言， 细胞包膜的外膜和肽聚糖层是耐药表型的关键，其中一个 一层弥补另一层的缺陷。而组装外膜和细胞壁的酶则是 众所周知，A。鲍曼不动杆菌编码独特的调节机制以控制它们响应压力的活性。 在这个建议中，我们将解决三个重要的问题，以了解内在的抗生素耐药性在A。 鲍曼不动杆菌。这些问题将探讨肽聚糖和外膜组装之间的关系， 在革兰氏阴性菌中知之甚少。这项工作的结果将使我们能够建立一个内在的模型， 因素在A.鲍曼不动杆菌，导致多药耐药性，并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 卫生研究所的使命，旨在促进基本发现，以减少人类疾病。

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.