Novel linear lipopeptide paenipeptins sensitize multidrug-resistant Gram-negative pathogens to antibiotics

项目摘要 美国传染病学会最近确定了一系列耐药病原体， 避开大多数抗菌剂的作用。这些有问题的病原体包括屎肠球菌， 金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和 肠杆菌属，它们统称为ESKAPE。因此，迫切需要 开发有效的抗生素，以跟上抗生素耐药性。 类肽素是一种新型的人工合成线性脂肽，由9个氨基酸残基和1个脂肪酰基组成 在N-末端的基团。它们与克拉霉素联合使用时对革兰氏阴性杆菌显示出高度有效的活性。 体外阴性病原体。本项目的总体目标是开发新型线性脂肽抗生素 增效剂，可以与FDA批准的抗生素共同使用，以扩大其抗菌活性。 谱和增强抗生素活性，用于治疗与多粘菌素耐药相关的感染 和碳青霉烯类耐药病原体。为实现这一目标，确定了以下两个目标。 目的1：评价Paenipeptin类似物与克拉霉素在体外对A 大量碳青霉烯类耐药临床分离株，并探讨协同作用的机制。 目的2：开发用于局部递送paenipeptin-克拉霉素混合物的载抗菌剂水凝胶， 局部治疗伤口感染。

PROJECT SUMMARY The Infectious Diseases Society of America recently identified a list of antibiotic-resistant pathogens that can escape the effect of most antimicrobial agents. These problematic pathogens include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., which are collectively abbreviated as ESKAPE. Therefore, there is an urgent need to develop effective antibiotics to keep up with antibiotic resistance. Paenipeptins are novel synthetic linear lipopeptides, which are made of 9 amino acid residues and a fatty acyl group at the N-terminus. They showed highly potent activity in combination with clarithromycin against Gram- negative pathogens in vitro. The overall goal of this project is to develop novel linear lipopeptide antibiotic potentiators, which can be co-administered with FDA-approved antibiotics, to expand their antimicrobial spectrum and enhance the antibiotic activity for the treatment of infections associated with polymyxin-resistant and carbapenem-resistant pathogens. To achieve this goal, the following two aims are set. Aim 1: Evaluate the synergistic effect between paenipeptin analogues and clarithromycin in vitro against a large number of carbapenem-resistant clinical isolates and investigate the mechanism of synergism. Aim 2: Develop antimicrobial-loaded hydrogels for localized delivery of paenipeptin-clarithromycin mixture for topical treatment of wound infections.