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

背景：世界正面临着来自细菌出现的巨大且日益严重的威胁 ‘超级细菌’。如果细菌继续以目前的速度和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，可能会产生灾难性的成本 医疗保健和全球社会。世界各地的许多医院都经历了感染的暴发 由耐多药铜绿假单胞菌、鲍曼不动杆菌和克雷伯氏菌引起 肺炎。所有这些病原体都在国际开发署的六种最优先的危险细菌名单上 需要紧急关注以发现新的抗生素。多粘菌素(即粘菌素和多粘菌素B)被用作 治疗由这些非常有问题的革兰氏阴性病原体引起的感染的最后一线。不幸的是， 多粘菌素的肾毒性和抗肺部感染疗效差，阻碍了其临床应用。 对药物动力学的限制。不幸的是，已有多粘菌素的质粒携带耐药性的报道。 最近。本质上，多粘菌素耐药意味着完全缺乏治疗致命疾病的抗生素。 由这些革兰氏阴性细菌引起的感染。显然，开发新的抗生素是当务之急 需要的。这三种革兰氏阴性细菌都是这个项目的重点。研究设计：建筑 在我们过去17年的系统多粘菌素药理研究基础上，这个项目将采用我们的 合理发展构效关系(SAR)和构毒关系(STR)新模型 新型、更安全的多粘菌素样脂多肽，靶向包括多粘菌素抗性在内的革兰氏阴性“超级细菌” 分离株。具体目标是：(1)利用我们成熟的脂肽药物化学平台 设计、合成并对近300个新的抗MDR K脂肽进行了微生物学评价。 肺炎、铜绿假单胞菌和鲍曼不动杆菌；(2)根据急性感染情况进行莱氏杆菌选择 并使IND应用程序受益；以及(4)开发主要候选人(和后备人员) S根据啮齿动物和非啮齿动物对其稳定性、毒性、PK和PK/PD的评价 来自特定目标4的结果也将提供基本的疗效和毒性数据来支持 死了。尽管这超出了这次RFA的范围，但我们非常热情 D候选人将被纳入IND-Enabling研究，资金支持来自 重大意义：我们的创新方案将开发出亟需的更安全、更有效的方案 目前由革兰氏阴性“超级细菌”引起的全球健康危机。

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'.