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

描述(由申请者提供)：正如美国传染病学会在“坏细菌，没有药物”活动中强调的那样，“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，即所谓的‘超级细菌’。”世界各地的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，这三种病原体是6种最优先的危险“ESKAPE”病原体，需要最迫切地关注才能发现新的抗生素。可悲的是，在未来的许多年里，不会有新的抗生素来对抗这些革兰氏阴性‘超级细菌’。多粘菌素(即多粘菌素B和粘菌素)现在被用作这些非常有问题的MDR病原体的最后治疗方法。最不幸的是，最近出现多粘菌素耐药性的报道越来越多。从本质上说，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耐药(PDR)革兰氏阴性细菌引起的危及生命的感染。研究设计：本项目将把系统药理学应用于抗生素药代动力学/药效学(PK/PD)，以确定多粘菌素与FDA批准的非抗生素药物针对PDR铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌的新组合。我们的总体假设是，已确定的多粘菌素-非抗生素组合将以最小的耐药性发展协同杀死革兰氏阴性‘超级细菌’，系统药理学与抗菌素PK/PD模型的结合将阐明宿主-病原体-药物之间协同作用的潜在机制(S)。我们的具体目标是：(1)寻找针对铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌的新型多粘菌素-非抗生素组合；(2)研究活性多粘菌素-非抗生素组合的体外PK/PD；(3)利用中空纤维感染模型评价活性组合对多粘菌素耐药性的协同杀伤和抑制作用，并进行组学研究；(4)利用小鼠感染模型验证最有效组合的概念，并进行组学综合研究以了解宿主-病原体-药物的相互作用；对多粘菌素-非抗生素组合进行系统药理网络分析和PK/PD数学建模。转录组学、蛋白质组学和代谢组学将被用于研究宿主、病原体和药物之间的相互作用。总而言之，这些研究将确定多粘菌素-非抗生素的最佳组合(外加一个备份)，用于进一步的药理学评估。意义：该项目为新的多粘菌素组合的开发带来了巨大的希望。由于所有药物都已获得FDA的批准，我们的多学科方法将提供一个快速且具有成本效益的解决方案，以对抗这些非常有问题的革兰氏阴性‘超级细菌’。总体而言，该项目针对的是全球迫切的未得到满足的医疗需求，即缺乏新的抗生素。

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.