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

项目摘要/摘要 多重药物和广泛耐药的革兰氏阴性细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出现的危急威胁病原菌 臭名昭著的是它有能力迅速产生内在的多药耐药性。鲍曼不动杆菌导致医院获得性感染 感染，表现为菌血症、尿路和伤口感染。在美国，估计有60%的 医院获得性鲍曼不动杆菌感染是多重耐药的，通常包括碳青霉烯类耐药， 使粘菌素成为“最后的”治疗选择。然而，粘菌素耐药性也出现了。有一个 迫切需要了解促进鲍曼不动杆菌耐药表型的内在机制 指导可供选择的抗菌策略。我们的初步工作已经确定了促进收购的因素 鲍曼不动杆菌的多重耐药，包括碳青霉烯类和粘菌素耐药。具体地说， 细胞膜的外膜和肽聚糖层是耐药表型的关键，其中一种 层补偿另一层中的缺陷。而组装外膜和细胞壁的酶是 众所周知，鲍曼不动杆菌编码了独特的调节机制来控制它们在应对压力时的活动。 在这项提案中，我们将解决三个重要问题，以了解A。 鲍曼尼。这些问题将探索肽聚糖与外膜组装的关系，它 在革兰氏阴性细菌中知之甚少。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药耐药的因素将有助于设计联合用药方案 它针对两个基本层面，从而排除了阻力；因此，我们的发现支持国家 健康研究所的使命，旨在促进减少人类疾病的基本发现。

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.