Novel Phage Display Platforms to Overcome Colistin Resistance

克服粘菌素耐药性的新型噬菌体展示平台

基本信息

批准号：
10165742
负责人：
Jianmin Gao
金额：
$ 29.74万
依托单位：
BOSTON COLLEGE
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：
2019-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165742
关键词：
Acinetobacter baumannii Animal Model Animals Antibiotic Resistance Antibiotics Attention Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacteriophages Binding Cell surface Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Clinical Colistin Detection Electrostatics Eosine Yellowish Gram-Negative Bacteria Gram-Negative Bacterial Infections Hydrophobicity In Vitro Infection Libraries Lipopolysaccharides Lipoproteins Membrane Modification Molecular Molecular Probes Multi-Drug Resistance Parents Peptide Antibiotics Peptide Library Peptides Periodicity Phage Display Pharmaceutical Preparations Reporting Research Resistance Resort Serum Societies Specificity Testing Toxic effect Toxin Conjugates United States Work bacterial resistance bactericide carbapenem resistance cell envelope colistin resistance functional group improved in vitro testing in vivo nephrotoxicity new technology novel novel strategies pathogen pathogenic bacteria resistant strain scaffold screening success tool

项目摘要

Novel Phage Display Platforms to Overcome Colistin Resistance Project Summary Antibiotic resistance of bacterial pathogens poses a serious threat to our society. According to a recent CDC report, in the United States alone, there are over 2 million cases of infection and over 23,000 deaths every year that are caused by antibiotic-resistant strains of bacteria. Among these, colistin resistance of gram-negative bacteria demands urgent attention. Colistin is an old antibiotic first approved for clinical use several decades ago. It had been recently revived as the last hope antibiotic to treat carbapenem-resistant gram-negative infections. Colistin resistance are known to arise from cell envelope remodeling, ranging from subtle derivatizations of lipopolysaccharide (LPS) to total replacement of LPS with lipoproteins. Our recent work has shown that the remodeled cell envelope underlying colistin resistance can be targeted by screening novel peptide libraries on phage. Building on these preliminary studies, we propose to develop additional novel phage libraries that incorporate non-proteinogenic functional groups. Screening of these libraries against colistin-resistant bacteria is expected to reveal highly potent and specific binders for these deadly pathogens. We will further develop peptide-antibiotic conjugates for effective eradication of these colistin-resistant bacterial pathogens. The efficacy of the peptide-antibiotic conjugates will be assessed in vitro and in animal models. Research Strategy Page 1

新颖的噬菌体展示平台以克服抗体蛋白抗性项目摘要细菌病原体的抗生素耐药性对我们的社会构成了严重威胁。根据最近的CDC 报告，仅在美国，每年就有超过200万例感染和23,000多人死亡由细菌的抗生素菌株引起的。其中，革兰氏阴性菌属抗性细菌需要紧急关注。 Colistin是一种旧的抗生素，首先被批准用于临床使用数十年前。它最近被复兴为抗碳青霉烯的最后一个希望抗生素的抗生素感染。已知结肠蛋白抗性是由细胞包膜重塑产生的，范围从微妙脂多糖（LPS）衍生物用脂蛋白总替代LPS。我们最近的工作有表明可以通过筛选新颖的靶向菌丝毒素耐药性的重塑细胞包膜。噬菌体上的肽库。在这些初步研究的基础上，我们建议开发其他新颖的新颖噬菌体文库结合了非蛋白原官能团。筛选这些图书馆反对预计可抗结肠素的细菌将为这些致命的病原体揭示高度有效和特定的粘合剂。我们将进一步开发肽 - 抗生素结合物，以有效根除这些抗colistin的细菌病原体。将在体外和动物模型中评估肽 - 抗生素结合物的功效。研究策略第1页