Solving a Novel Multidrug Resistance Puzzle: Complete Loss of Lipooligosaccharide

 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组成的不对称双层， 脂多糖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，并且靶向外膜中的必需脂寡糖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脂多糖的生物合成，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，因为脂寡糖和脂多糖以前被认为是革兰氏阴性细菌生存力所必需的，但这种多药耐药机制证明它不是必需的。导致这种多药耐药表型的机制尚不清楚，治疗方案尚未探索。该提案的总体目标是表征和理解一种新的多药耐药机制。本提案的具体目的是（i）了解脂寡糖完全缺失的遗传要求和（ii）表征脂寡糖完全缺失后改变的外膜渗透性屏障。这项工作的完成将有助于一个重要的知识体系的重要性脂寡糖或脂多糖在革兰氏阴性菌，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。

 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 or lipopolysaccharide. Acinetobacter baumannii is a Gram-negative nosocomial pathogen that thrives in healthcare settings because of its ability to develop resistance to antibiotics. Multidrg resistant A. baumannii have become widespread over the past decade and last-line antibiotics such as colistin, which target the essential lipooligosaccharide 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 shut down lipopolysaccharide biosynthesis to develop resistance to colistin and many other commonly prescribed antibiotics. This finding is surprising because lipooligosaccharide and lipopolysaccharide were previously thought to be required for Gram-negative bacterial viability, but this multidrug resistance mechanism proves that it is not essential. Mechanisms that contribute to this multidrug resistance phenotype are not understood and treatment options have not been explored. 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 lipooligosaccharide and (ii) to characterize the altered outer membrane permeability barrier after complete loss of lipooligosaccharide. Completion of this work will contribute an essential body of knowledge to the essentiality of lipooligosaccharide or lipopolysaccharide in Gram-negative bacteria and provide understanding of a molecular mechanism 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.