Harnessing bacteriophages as natural predators to combat the superbugs: a pulmonary drug delivery approach

 描述（由申请人提供）：正如美国传染病协会（IDSA）在“Bad Bugs，No Drugs”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）铜绿假单胞菌引起的感染爆发，这是IDSA确定的六种最优先的危险“ESKAPE”微生物之一，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，都没有针对MDR铜绿假单胞菌的新型抗生素。多粘菌素（即粘菌素和多粘菌素B）现在被用作由这些非常成问题的MDR病原体引起的感染的“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这些革兰氏阴性菌引起的危及生命的感染。 研究设计：我们的研究策略包括R21和R33阶段。该项目的总体目标是利用吸入的噬菌体作为自然捕食者来对抗呼吸道感染中的超级细菌。我们的过度假设是吸入递送作为气雾剂的NH4将为肺部MDR感染提供安全有效的局部治疗。R21阶段包括两个特定目的：（1）生产用于吸入气雾剂递送至肺部的新型噬菌体粉末制剂，以及（2）通过理化表征和概念验证功效研究确定这些phge制剂的有效性和实用性。如果满足R21阶段的特定里程碑，则R33阶段将（1）阐明负责稳定噬菌体粉末制剂的机制，并评价噬菌体吸入制剂的储存稳定性[具体目标3]，同时检查吸入噬菌体制剂的药代动力学和潜在毒性[具体目标4]。最后在 将使用动物感染模型进行吸入噬菌体制剂的体内功效研究[具体目标5]。总之，这些研究将确定最佳的噬菌体制剂（加上一个备份），用于进一步的临床前药理学评价。由于药物已经在临床上使用，因此将我们的研究结果迅速转化为临床的潜力很大。 意义：该项目为开发一种新的用于MDR铜绿假单胞菌引起的呼吸道感染的噬菌体疗法带来了巨大的希望。我们的跨学科方法将为吸入性噬菌体治疗提供最快的跟踪和成本效益的临床解决方案，以打击非常有问题的革兰氏阴性“超级细菌”。总体而言，该项目针对全球未满足的紧急医疗需求，与2014年NIAID抗菌素耐药性研究战略方法完全一致。

 DESCRIPTION (provided by applicant): As highlighted in the 'Bad Bugs, No Drugs' campaign by the Infectious Diseases Society of America (IDSA), "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 of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, one of the six top-priority dangerous "ESKAPE" microorganisms identified by the IDSA that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against MDR P. aeruginosa will be available for many years to come. Polymyxins (i.e. colistin and polymyxin B) are now being used as the `last-line' of therapy for infections caused by 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 Gram-negative bacteria. Research Design: Our research strategy includes R21 and R33 phases. The overall objective of this project is to harness inhaled bacteriophages as natural predators to combat the superbugs in respiratory infections. Our over-arching hypothesis is that inhalation delivery of phages as an aerosol will provide a safe and efficacious local treatment for MDR infections in the lungs. R21 phase includes two Specific Aims: (1) to produce novel phage powder formulations for inhalation aerosol delivery to the lungs, and (2) to establish the validity and utility of these phge formulations by physicochemical characterization and proof-of- concept efficacy study. If the specific milestones in R21 phase are met, the R33 phase will (1) elucidate the mechanism responsible for stabilization of phages in powder formulations, and evaluate the storage stability of the phage inhalation formulations [Specific Aim 3], and in parallel, examine the pharmacokinetics and potential toxicity of inhaled phage formulations [Specific Aim 4]. Finally, in vivo efficacy studies of inhaled phage formulations will be conducted using animal infection models [Specific Aim 5]. Together, these studies will identify the best phage formulation (plus one backup) for further pre-clinical pharmacological evaluations. As phages are already used clinically, there is great potential to rapidly translate our research findings to the clinic. Significance: This project holds great promise for the development of a novel phage therapy for respiratory infections caused by MDR P. aeruginosa. Our inter-disciplinary approach will provide the fastest track and cost effective clinical solutions for inhaled phage therapy to combat the very problematic Gram-negative `superbug'. Overall, this project targets an urgent global unmet medical need and it aligns perfectly with the 2014 NIAID Antimicrobial Resistance Research Strategic Approaches.