Targeting the Urgent Need for New Antibiotics against Gram-negative ‘Superbugs’

背景：世界正面临着来自细菌的出现的巨大和日益增长的威胁。 超级细菌。如果细菌继续以目前的速度对多种抗生素产生耐药性， 在抗生素管道继续枯竭的同时， 全球医疗保健和社会。世界各地的许多医院都经历了感染的爆发 由多重耐药（MDR）铜绿假单胞菌、鲍曼不动杆菌和克雷伯菌引起 肺炎。所有这些病原体都在IDSA的六种最优先危险细菌的“打击名单”上， 迫切需要注意发现新的抗生素。多粘菌素（即粘菌素和多粘菌素B）用作 治疗由这些非常成问题的革兰氏阴性病原体引起的感染的“最后一线”治疗。不幸的是， 多粘菌素的临床应用受到其肾毒性和对肺部感染的不良功效的阻碍 药代动力学限制。不幸的是，质粒携带的耐药性多粘菌素已报告 最近从本质上讲，多粘菌素耐药性意味着完全缺乏抗生素来治疗致命的 由这些革兰氏阴性菌引起的感染。显然，开发新的抗生素是迫切的。 needed.所有这三种革兰氏阴性细菌都是该项目的重点。研究设计：建筑 在我们过去17年系统的多粘菌素药理学研究的基础上，本项目将利用我们的 新型构效关系（SAR）和构毒关系（STR）模型，合理开发 靶向革兰氏阴性“超级细菌”的新型、更安全的多粘菌素样脂肽， 分离株具体目的是：（1）利用我们完善的脂肽药物化学平台， 设计、合成和微生物学评价约300种抗MDR K的新型脂肽。 pneumoniae、铜绿假单胞菌和A.（2）根据急性感染情况进行叶霉病菌筛选， 有利于IND申请;（4）开发主要候选人（和备份） 基于使用啮齿动物和非啮齿动物进行的稳定性、毒性、PK和PK/PD评价， 具体目标4的结果还将提供基本的疗效和毒性数据，以支持 死了尽管这超出了RFA的范围，但我们非常热情 d候选人将被纳入IND赋能研究，并得到以下方面的资助： ificance：我们的创新建议将开发急需的更安全，更有效的 目前的全球健康危机是由革兰氏阴性“超级细菌”引起的。

Background: The world is facing an enormous and growing threat from the emergence of bacterial `superbugs'. If bacteria continue developing resistance to multiple antibiotics at the present rate and at the same time the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. All of these pathogens are on the IDSA `hit list' of the six top-priority dangerous bacteria that require urgent attention to discover new antibiotics. Polymyxins (i.e. colistin and polymyxin B) are used as the `last-line' of therapy for infections caused by these very problematic Gram-negative pathogens. Unfortunately, the clinical utility of polymyxins is hindered by their nephrotoxicity and poor efficacy against lung infections due to pharmacokinetic limitations. Unfortunately, plasmid-borne resistance to polymyxins has been reported recently. In essence, polymyxin resistance implies a total lack of antibiotics for treatment of deadly infections caused by these Gram-negative bacteria. Clearly, the development of new antibiotics is urgently needed. All three of these Gram-negative bacteria are the focus of this project. Research Design: Building upon our systematic polymyxin pharmacology research over the last 17 years, this project will employ our novel structure-activity relationship (SAR) and structure-toxicity relationship (STR) models to rationally develop novel, safer polymyxin-like lipopeptides that target Gram-negative `superbugs' including polymyxin-resistant isolates. The Specific Aims are: (1) To employ our well established lipopeptide medicinal chemistry platform to design, synthesize and microbiologically evaluate approximately 300 novel lipopeptides against MDR K. pneumoniae, P. aeruginosa and A. baumannii; (2) To conduct leawdillciamnpdriodvaete selection based upon acute conduc nd benefit the IND application; and (4) To develop the lead candidate (and a back-up) s based upon evaluations of the stability, toxicity, PK and PK/PD using rodent and non- ults from Specific Aim 4 will also provide essential efficacy and toxicity data to support dies. Even though it is beyond the scope of this RFA, we are very enthusiastic d candidate will be taken into IND-enabling studies with financial support from ificance: Our innovative proposal will develop much-needed safer and more efficacious t the current global health crisis caused by Gram-negative `superbugs'.