New Tricks for 'Old' Drugs: PK/PD of Polymyxin Nonantibiotic Combinations

描述（由申请人提供）：正如美国传染病协会在“坏虫子，没有药物”运动中所强调的那样，“制药管道中根本没有足够的新药来跟上耐药细菌感染的步伐，所谓的“超级细菌”。“全球许多医院都经历了由多药耐药（MDR）铜绿假单胞菌，鲍曼不动杆菌和肺炎克雷伯菌引起的疫情，这是6种最优先的危险“ESKAPE”病原体中的三种，需要最紧迫的关注来发现新的抗生素。可悲的是，在未来的许多年里，都不会有针对这些革兰氏阴性“超级细菌”的新型抗生素。多粘菌素（即多粘菌素B和粘菌素）目前正被用作这些非常有问题的MDR病原体的最后一线治疗。最不幸的是，多粘菌素耐药性的出现最近越来越多地被报道。从本质上讲，对多粘菌素的耐药性意味着完全缺乏抗生素来治疗由这些泛耐药（PDR）革兰氏阴性菌引起的危及生命的感染。研究设计：本项目将系统药理学应用于抗生素药代动力学/药效学（PK/PD），以确定新的多粘菌素与FDA批准的非抗生素药物联合治疗PDR铜绿假单胞菌，A。baumannii和K.肺炎。我们的过度假设是，所鉴定的多粘菌素-非抗生素组合将协同杀死革兰氏阴性“超级细菌”，而耐药性的发展最小，并且系统药理学与抗微生物PK/PD建模的整合将阐明宿主-病原体-药物之间协同相互作用的潜在机制。我们的具体目标是：（1）确定新的多粘菌素-非抗生素组合对泛耐药铜绿假单胞菌，A。baumannii和K.肺炎;（2）研究活性多粘菌素-非抗生素组合的体外PK/PD;（3）使用中空纤维感染模型评价活性组合在2周治疗期间对多粘菌素抗性的协同杀伤和抑制，并进行组学研究;（4）使用小鼠感染模型证明最有效组合的概念验证，并进行综合组学研究，以了解宿主-病原体-药物相互作用;和（5）对多粘菌素-非抗生素组合进行系统药理学网络分析和PK/PD数学建模。转录组学、蛋白质组学和代谢组学将用于研究宿主、病原体和药物之间的相互作用。总之，这些研究将确定最佳的多粘菌素-非抗生素组合（加上一个备份），以进一步的药理学评价。意义：该项目为开发新型多粘菌素组合提供了巨大的希望。由于所有药物都已获得FDA批准，我们的多学科方法将提供快速和具有成本效益的解决方案，以打击这些非常有问题的革兰氏阴性“超级细菌”。总的来说，该项目针对全球迫切的未满足的医疗需求，缺乏新的抗生素。

DESCRIPTION (provided by applicant): As highlighted in the 'Bad Bugs, No Drugs' campaign by the Infectious Diseases Society of America, "There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial infections, so-called 'superbugs'." Numerous hospitals worldwide have experienced outbreaks caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, three of the 6 top-priority dangerous "ESKAPE" pathogens that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against these Gram-negative 'superbugs' will be available for many years to come. Polymyxins (i.e. polymyxin B and colistin) are now being used as the last-line therapy for these very problematic MDR pathogens. Most unfortunately, the emergence of polymyxin resistance has been increasingly reported recently. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these pandrug-resistant (PDR) Gram-negative bacteria. Research Design: This project will apply systems pharmacology to antibiotic pharmacokinetics/pharmacodynamics (PK/PD) to identify novel polymyxin combinations with FDA-approved nonantibiotic drugs against PDR P. aeruginosa, A. baumannii and K. pneumoniae. Our over-arching hypothesis is that the identified polymyxin-nonantibiotic combinations will synergistically kill Gram-negative 'superbugs' with minimal development of resistance, and integration of systems pharmacology with antimicrobial PK/PD modeling will elucidate the underlying mechanism(s) of the synergistic interaction between host-pathogen-drug. Our specific aims are to: (1) Identify novel polymyxin-nonantibiotic combinations against pandrug-resistant P. aeruginosa, A. baumannii and K. pneumoniae; (2) Investigate the in vitro PK/PD of active polymyxin-nonantibiotic combinations; (3) Evaluate the synergistic killing and suppression of polymyxin resistance by the active combinations over 2-week treatment using hollow fiber infection model and conduct omics studies; (4) Demonstrate proof-of-concept for the most active combinations using mouse infection models and conduct integrated omics studies to understand the host-pathogen-drug interactions; and (5) Conduct systems pharmacology network analysis and PK/PD mathematical modeling on the polymyxin- nonantibiotic combinations. Transcriptomics, proteomics and metabolomics will be utilized to investigate the interaction between host, pathogen and drug. Together, these studies will identify the best polymyxin-nonantibiotic combination (plus one backup) for further pharmacological evaluations. Significance: This project holds great promise for development of novel polymyxin combinations. As all drugs have already been approved by FDA, our multi-disciplinary approach will provide a fast-track and cost-effective solution to combat these very problematic Gram-negative 'superbugs'. Overall, this project targets the urgent global unmet medical need, lack of new antibiotics.