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

新型线性脂肽paenipeptins使多重耐药革兰氏阴性病原体对抗生素敏感

• 批准号: 9808875
• 负责人: En Huang
• 金额: $ 22.65万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808875
• 关键词: Acinetobacter baumannii; Adjuvant; Americas; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Area; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Carbapenems; Cations; Centers for Disease Control and Prevention (U.S.); Clarithromycin; Clinical; Combating Antibiotic Resistant Bacteria; Combined Antibiotics; Communicable Diseases; Data; Development; Drug resistance; Drug-resistant Campylobacter; Enterobacter; Enterococcus faecium; Escherichia coli; FDA approved; Formulation; Gelatin; Generations; Goals; Gram-Negative Bacteria; High Pressure Liquid Chromatography; Human; Hydrogels; Hydrophobicity; In Vitro; Infection; Kinetics; Klebsiella pneumonia bacterium; Lipopolysaccharides; Medical; Membrane; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Mus; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physicians; Polymyxin Resistance; Polymyxins; Predisposition; Property; Pseudomonas aeruginosa; Public Health; Reporting; Research; Resistance; Resort; Risk; Serum; Skin wound; Societies; Speed; Staphylococcus aureus; Structure-Activity Relationship; Testing; Therapeutic; Topical application; Toxic effect; Transmission Electron Microscopy; Treatment Efficacy; Vancomycin resistant enterococcus; Wound Infection; acyl group; analog; antimicrobial; antimicrobial drug; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; carbapenemase; combat; cytotoxic; drug discovery; drug resistant pathogen; experience; improved; in vivo; methicillin resistant Staphylococcus aureus; multidrug-resistant Pseudomonas aeruginosa; novel; pathogen; pathogenic bacteria; skin irritation; success; synergism; systemic toxicity; wound

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.

项目总结 美国传染病学会最近确定了一份抗药性病原体名单，这些病原体可以 逃避大多数抗菌剂的影响。这些有问题的病原体包括粪肠球菌， 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，统称为ESKAPE。因此，迫切需要 开发有效的抗生素以应对抗生素耐药性。 派尼肽是由9个氨基酸残基和1个脂肪酰基组成的新型人工合成的线性脂肽。 在N端的群组。它们与克拉霉素联合使用对革兰氏杆菌显示出很强的活性。 体外培养阴性病原体。本项目的总体目标是开发新型线型脂肽抗生素。 增强剂，可以与FDA批准的抗生素联合使用，以扩大其抗菌力 治疗多粘菌素耐药相关感染的谱和增强抗生素活性 以及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：评价派尼肽素类似物与克拉霉素的体外协同抗肿瘤作用。 大量临床分离株对碳青霉烯类耐药，并探讨其协同作用机制。 目的2：研制抗菌水凝胶，用于派尼肽-克拉霉素混合物的局部给药 伤口感染的局部治疗。