Discovery of Polymyxin-based Antibacterial Agents Active Against Multi-Drug Resis

项目摘要 背景：多重耐药病原菌的出现代表了严重的， 对人类生命和国家医疗保健系统的威胁越来越大。这些 超级昆虫 现在杀死10万人S 据估计，这将使美国的医疗保健成本增加200亿美元。特别是 革兰氏阴性菌株如肺炎克雷伯氏菌，大肠杆菌， 鲍曼不动杆菌和铜绿假单胞菌与快速传播的NDM-1表型 我们非常关注对于许多革兰氏阴性感染，粘菌素（多粘菌素E）仍然是 唯一的选择 最后手段，其中碳青霉烯类不再具有活性，以及替加环素的病例 据报道，抵抗。 目的和目标：我们的目标是生产新的抗生素，基于粘菌素， 耐 超级细菌 而且安全性比现在的更好 最后的手段 抗生素的 研究将提供针对耐药致病菌的新型候选药物， 提供了一个详细的科学认识的起源和机制， 毒性（肾毒性）。我们将详细了解粘菌素如何杀死细菌。 从长远来看，开发的肾毒性分析方法将证明在所有领域都有价值 药物研究，从而提供了工具，为药物肾毒性和更一般的药物肾毒性 筛选新的粘菌素衍生物将积极对抗严重的革兰氏阴性菌超级 超级细菌并攻击细菌的药物敏感菌株和耐药菌株。 途径和方法：本计划将使用世界上第一个快速合成方法， 1，400个粘菌素类似物，用于结构活性和结构毒性的前所未有的系统研究 关系。这些新型化合物将针对耐药的 革兰氏阴性细菌，特别是NDM-1菌株，然后评价作用模式、稳定性， 细胞毒性和肾毒性。还将分析它们与细菌膜的结合情况， 分子靶点（脂质A）。这将导致药物作用的体内原理验证， 药代动力学研究，用于选择化合物进行未来的临床前评价。

Project Summary Background: The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to human lives and national healthcare systems. These supebugs now kill 100,000s of people each year and are estimated to add $20bn in healthcare costs in the US. In particular, the expansion of Gram-negative strains such as Klebsiella pneumonia, Escherichia coli, Acinetobacterbaumannii and Pseudomonasaeruginosa and the rapidly spreading NDM-1 phenotypes are of grave concern. For many of these Gram-negative infections, colistin (polymyxin E) remains the only option of last resort, where the carbapenems are no longer active, and cases of tigecycline resistance have been reported. Aims & Objectives: We aim to produce new antibiotics, based on colistin, that are active against resistant super-bugs and that have better safety profiles than current last-resort antibiotics. The research will deliver novel drug-candidates targeted at resistant pathogenic bacteria, and will also provide a detailed scientific understanding of the origins and mechanisms of antibiotic-induced kidney toxicity (nephrotoxicity).We will develop a detailed understanding of how colistin works to kill bacteria. In the longer term, the assays developed for profiling of nephrotoxicity will prove valuable in all areas of drug research, thus providing tools for both antibiotic-renal and more general drug-renal toxicity screening. The new colistin derivatives will be active against the serious Gram-negative super superbugs and attack both drug-sensitive and drug-resistant strains of the bacteria. Approach & methods: This program will use aworld first synthetic method for the rapid synthesis of 1,400colistin analogs for an unprecedented systematic investigation of structure-activity and structuretoxicity relationships. These novel compounds will be optimized for activity against drug-resistant Gram-negative bacteria, in particular NDM-1 strains, and then evaluated for mode of action, stability, cell toxicity and nephrotoxicity. They will also be profiled for binding to the bacterial membranes and molecular target (Lipid A). This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation.