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

发现具有多药耐药性的多粘菌素类抗菌剂

• 批准号: 8825051
• 负责人: Matthew A Cooper
• 金额: $ 32.39万
• 依托单位: UNIVERSITY OF QUEENSLAND
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-04 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825051
• 关键词: Acinetobacter; Affinity; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Binding; Biological Assay; Carbapenems; Cells; Clinical; Colistin; Confocal Microscopy; Data; Development; Drug Kinetics; Drug effect disorder; Drug resistance; Drug-sensitive; Effectiveness; Electrons; Escherichia coli; Evaluation; Fosfomycin; Future; Gram-Negative Bacteria; Health; Health Care Costs; Healthcare Systems; Human; Image; In Vitro; Infection; Investigation; Kidney; Klebsiella pneumonia bacterium; Lactamase; Lactams; Lead; Life; Lipid A; Membrane; Methods; Molecular Target; Multi-Drug Resistance; Nuclear Magnetic Resonance; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Polymyxin Resistance; Polymyxins; Pseudomonas aeruginosa; Public Health; Reporting; Research; Resistance; Resolution; Resort; Safety; Scanning; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Testing; Toxic effect; Transmission Electron Microscopy; Work; analog; base; carbapenem resistance; dosage; drug candidate; drug development; drug resistant bacteria; improved; in vivo; kidney cell; killings; nephrotoxicity; novel; pathogenic bacteria; pre-clinical; preclinical study; programs; rapid technique; research clinical testing; resistance mechanism; resistant strain; screening; tigecycline; tool

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Gram-negative infections, colistin (polymyxin E) remains the only option of last resort, where the carbapenems are no longer active, and cases of tigecycline resistance have been reported.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.

项目概要 背景：多重耐药病原菌的出现代表了一个严重的、 对人类生命和国家医疗保健系统的威胁日益严重。这些超级细菌现已杀死 100,000 只细菌 每年都会增加 200 亿美元的医疗费用，预计会增加美国 200 亿美元的医疗费用。特别是， 革兰氏阴性菌株的扩增，例如肺炎克雷伯菌、大肠杆菌、 鲍曼不动杆菌和铜绿假单胞菌以及快速传播的 NDM-1 表型 令人严重关切。对于许多革兰氏阴性菌感染，粘菌素（多粘菌素 E）仍然是首选 最后的唯一选择，碳青霉烯类不再具有活性，以及​​替加环素的情况 有报道称存在耐药性。 目的和目标：我们的目标是生产基于粘菌素的新型抗生素，该抗生素可有效对抗 具有抗药性的超级细菌，并且比目前的最后手段抗生素具有更好的安全性。这 研究将提供针对耐药病原菌的新型候选药物，并且还将 提供对抗生素诱发肾病的起源和机制的详细科学理解 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，为分析肾毒性而开发的测定方法将在所有领域证明有价值 药物研究，从而为抗生素肾毒性和更一般的药物肾毒性提供工具 筛选。新的粘菌素衍生物将有效对抗严重的革兰氏阴性超级细菌 超级细菌并攻击药物敏感和耐药菌株。 途径与方法：本项目将采用世界首创的合成方法来快速合成 1,400 种粘菌素类似物，用于对结构活性和结构毒性进行前所未有的系统研究 关系。这些新型化合物将针对抗耐药性的活性进行优化 革兰氏阴性菌，特别是 NDM-1 菌株，然后评估作用方式、稳定性、 细胞毒性和肾毒性。还将对它们与细菌膜的结合进行分析， 分子靶标（脂质 A）。这将导致药物作用的体内原理验证和 药代动力学研究，用于选择化合物用于未来的临床前评估。