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Gram-negative infections, colistin (polymyxin E) remains the only option of last resort, where the carbapenems are no longer active, and cases of tigecycline resistance have been reported.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

项目摘要 背景：多重耐药病原菌的出现代表了一种严重和 对人类生命和国家医疗保健系统的威胁越来越大。这些超级细菌现在杀死了10万人 估计将在美国增加200亿美元的医疗成本。尤其是， 革兰氏阴性杆菌如肺炎克雷伯氏菌、大肠埃希菌、 鲍曼不动杆菌和铜绿假单胞菌与快速传播的NDM-1表型 都是令人严重关切的。对于许多革兰氏阴性感染，粘菌素(多粘菌素E)仍然是 在碳青霉烯类药物不再有效的情况下，以及替吉环素的情况下，唯一的最后选择 已经有抗药性的报道。 目标和目标：我们的目标是生产以粘菌素为基础的新抗生素，这些抗生素对 具有抗药性的超级细菌，比目前最后的抗生素具有更好的安全性。这个 研究将提供针对耐药病原体的新型候选药物，还将 对抗生素所致肾脏的起源和机制有详细的科学认识 毒性(肾毒性)：我们将详细了解粘菌素是如何杀灭细菌的。 从长远来看，为分析肾毒性而开发的分析方法将被证明在所有领域都有价值。 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了工具 放映。新的粘菌素衍生物将有效对抗严重的革兰氏阴性超级 超级细菌和攻击药物敏感和耐药菌株的细菌。 途径与方法：本项目将使用世界上第一个合成方法来快速合成 1,400个粘菌素类似物史无前例的结构-活性和结构毒性系统研究 两性关系。这些新化合物将针对抗药性进行优化。 革兰氏阴性菌，特别是NDM-1菌株，然后评估作用模式、稳定性、 细胞毒性和肾脏毒性。它们还将被配置为结合到细菌膜和 分子靶标(脂类A)。这将导致体内药物作用的原则证明和 用于未来临床前评估的化合物选择的药代动力学研究。