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 项目摘要 细菌病原体的抗生素耐药性对我们的社会构成严重威胁。根据疾控中心最近的一份报告， 据报道，仅在美国，每年就有超过200万例感染病例，超过23，000人死亡 是由抗药性细菌引起的其中革兰阴性杆菌对粘菌素耐药率最高， 细菌需要紧急关注。粘菌素是一种古老的抗生素，最初被批准用于临床几十年 前它最近被重新用作治疗碳青霉烯类耐药革兰氏阴性菌的最后希望抗生素 感染.已知粘菌素抗性是由细胞包膜重塑引起的，从细微的 从脂多糖（LPS）的衍生化到脂蛋白完全替代LPS。我们最近的工作 显示作为粘菌素抗性基础的重塑的细胞包膜可以通过筛选新的 噬菌体上的肽文库。在这些初步研究的基础上，我们建议开发新的 包含非蛋白质功能基团的噬菌体文库。筛选这些文库， 粘菌素抗性细菌有望揭示这些致命病原体的高效和特异性结合剂。 我们将进一步开发肽-抗生素缀合物，以有效根除这些耐粘菌素的细菌。 病原体将在体外和动物模型中评估肽-抗生素缀合物的功效。 研究策略第1页

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