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: 8267748
• 负责人: Matthew A Cooper
• 金额: $ 16.99万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267748
• 关键词: Acinetobacter; Acinetobacter baumannii; 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; Publishing; Reporting; Research; Resistance; Resolution; Resort; Safety; Scanning; Screening procedure; 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; tigecycline; tool

DESCRIPTION (provided by applicant): 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 100,000's 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, Acinetobacter baumannii and Pseudomonas aeruginosa 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Gram-negative infections, colistin (polymyxin E) remains the only option of 'last resort', where the carbapenems are no longer active, and cases of tigecycline resistance have been reported.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-resor' 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 a world first synthetic method for the rapid synthesis of 1,400 colistin analogs for an unprecedented systematic investigation of structure-activity and structure- toxicity 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. PUBLIC HEALTH RELEVANCE: Drug resistant bacteria, in particular the recently emergent NDM-1 strains, pose a serious and growing threat to human health in the USA and elsewhere. NDM-1 strains of carbapenem-resistant Gram-negative bacteria possess resistance mechanisms such that almost all antibiotics no longer protect patients from serious, life-threatening infection. We will modify one of the only two antibiotics (colistin) that remains activ against NDM-1 bacteria to reduce the drug's toxic effect on humans (kidney toxicity), and to increase its activity against the dangerous and rapidly spreading NDM-1 superbugs.

描述（由申请人提供）：多重耐药病原菌的出现对人类生命和国家医疗保健系统构成了严重且日益严重的威胁。这些“超级细菌”现在每年导致 10 万人死亡，估计会增加美国 200 亿美元的医疗费用。特别是革兰氏阴性菌株（如肺炎克雷伯菌、大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌）的扩张以及快速传播的 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“最后手段”的唯一选择，此时碳青霉烯类不再具有活性，并且已有替加环素耐药病例报告。目的和目标：我们的目标是生产基于粘菌素的新型抗生素，这些抗生素对耐药性“超级细菌”具有活性，并且比目前的“最后治疗”抗生素具有更好的安全性。该研究将提供针对耐药病原菌的新型候选药物，还将提供对抗生素引起的肾毒性（肾毒性）的起源和机制的详细科学理解。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药物研究的所有领域中证明有价值，从而为抗生素肾毒性和更一般的药物肾毒性筛选提供工具。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，并攻击药物敏感和耐药菌株。途径和方法：该项目将使用世界上第一个合成方法来快速合成 1,400 种粘菌素类似物，以对结构-活性和结构-毒性关系进行前所未有的系统研究。这些新型化合物将针对耐药革兰氏阴性菌（特别是 NDM-1 菌株）的活性进行优化，然后评估其作用方式、稳定性、细胞毒性和肾毒性。还将对它们与细菌膜和分子靶标（脂质 A）的结合进行分析。这将导致药物作用的体内原理验证和药代动力学研究，以选择用于未来临床前评估的化合物。 公共卫生相关性：耐药细菌，特别是最近出现的 NDM-1 菌株，对美国和其他地区的人类健康构成严重且日益严重的威胁。耐碳青霉烯类革兰氏阴性菌的 NDM-1 菌株具有耐药机制，几乎所有抗生素都不再能保护患者免受严重、危及生命的感染。我们将修改对 NDM-1 细菌保持活性的仅有的两种抗生素之一（粘菌素），以减少该药物对人类的毒性作用（肾毒性），并增强其对抗危险且快速传播的 NDM-1 超级细菌的活性。