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 细菌病原体对抗生素的耐药性对我们的社会构成了严重的威胁。根据最近的疾病控制与预防中心 据报道，仅在美国，每年就有超过200万例感染病例和超过2.3万人死亡 这是由耐抗生素的细菌菌株引起的。其中，革兰氏阴性菌对粘菌素耐药 细菌亟待关注。粘菌素是一种古老的抗生素，几十年来首次被批准用于临床 那是以前的事了。它最近被认为是治疗耐碳青霉烯类革兰氏阴性菌的最后希望的抗生素 感染。已知粘菌素抵抗是由细胞包膜重塑引起的，从微妙的 脂多糖(LPS)的衍生化，使其完全被脂蛋白取代。我们最近的工作是 结果表明，根据粘菌素抗性改造的细胞膜可以通过筛选新的靶点 噬菌体上的多肽文库。在这些初步研究的基础上，我们建议开发更多的小说 包含非蛋白生成功能基团的噬菌体文库。对这些文库进行对照筛选 粘菌素耐药性细菌预计将揭示这些致命病原体的高度有效和特定的结合体。 我们将进一步开发多肽-抗生素结合物，以有效根除这些对粘菌素具有耐药性的细菌。 病原体。这些多肽-抗生素结合物的有效性将在体外和动物模型中进行评估。 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