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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要美国传染病学会最近确定了一份耐抗生素病原体清单，这些病原体可以逃避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，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。 Paenipeptins 是新型合成线性脂肽，由 9 个氨基酸残基和一个脂肪酰基组成 N 末端的基团。它们与克拉霉素联合显示出高效的抗革兰氏阴性菌活性。体外阴性病原体。该项目的总体目标是开发新型线性脂肽抗生素增效剂，可与 FDA 批准的抗生素联合使用，以扩大其抗菌作用谱并增强抗生素活性，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。为了实现这一目标，制定了以下两个目标。目标 1：评估帕尼肽类似物和克拉霉素之间的体外协同作用大量耐碳青霉烯类临床分离株并探讨其协同作用机制。目标 2：开发负载抗菌剂的水凝胶，用于局部递送巴尼肽-克拉霉素混合物局部治疗伤口感染。