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

背景：世界正面临着一个巨大且日益严重的威胁 细菌“超级细菌”。如果细菌继续对多种抗生素产生抗药性 目前的速度，同时抗生素管道继续枯竭，在那里 可能会给全球医疗保健和社会带来灾难性的成本。多家医院 世界各地都爆发了由多药耐药(MDR)引起的感染 铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌。所有这些都是 病原体在IDSA的六种最优先的危险细菌中，需要 迫切需要发现新的抗生素。使用多粘菌素(即粘菌素和多粘菌素B) 作为治疗由这些非常有问题的革兰氏阴性菌引起的感染的最后一线 病原体。不幸的是，多粘菌素的肾毒性阻碍了其临床应用。 由于药代动力学限制，对肺部感染的疗效较差。不幸的是， 最近报告了多粘菌素的质粒型耐药。本质上，多粘菌素 耐药性意味着完全缺乏治疗致命感染所需的抗生素 这些革兰氏阴性细菌。显然，迫切需要开发新的抗生素。 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 根据我们过去17年来对多粘菌素的系统药理研究，这 该项目将采用我们的新型结构-活性关系(SAR)和结构-毒性 合理开发新的、更安全的多粘菌素样脂肽的关系(STR)模型 目标是革兰氏阴性‘超级细菌’，包括多粘菌素耐药菌株。具体目标是： (1)利用我们成熟的脂肽药物化学平台进行设计、合成 并对近300种新的抗多药耐药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)进行主要候选人遴选 基于动物模型的急性毒性、有效性和肾毒性，以及对An的MIC 扩大了临床分离株的范围。在目标2完成后，一个领先的候选脂肽和一个 将选择后备进行进一步开发(具体目标4)。(3)阐明作用机制 用系统研究我们的多粘菌素样脂多肽的抗菌活性和肾毒性 药理学和化学生物学。这些机理研究将改进我们的SAR/STR模型和 使IND应用程序受益；以及(4)开发支持IND的主要候选者(和后备人员 在评价稳定性、毒性、PK和PK/PD的基础上，用啮齿动物和非 啮齿动物模型。来自特定目标4的结果也将提供基本的疗效和毒性。 用于支持未来支持IND的研究的数据。尽管这超出了本RFA的范围，但我们 非常热情地认为，确定的主要候选人将被纳入支持IND的研究中 来自Rempex-Medco的财政支持。意义：我们的创新方案将得到发展 应对当前全球健康危机亟需的更安全、更有效的多粘菌素 由革兰氏阴性‘超级细菌’引起。

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 lead candidate selection based upon acute toxicity, efficacy and nephrotoxicity in animal models, and MICs against an extended panel of clinical isolates. Upon completion of Aim 2, a lead candidate lipopeptide and a back-up will be selected for further development (Specific Aim 4). (3) To elucidate the mechanisms of antibacterial activity and nephrotoxicity of our polymyxin- like lipopeptides using systems pharmacology and chemical biology. These mechanistic studies will improve our SAR/STR models and benefit the IND application; and (4) To develop the lead candidate (and a back-up) for IND-enabling studies based upon evaluations of the stability, toxicity, PK and PK/PD using rodent and non- rodent models. The results from Specific Aim 4 will also provide essential efficacy and toxicity data to support future IND-enabling studies. Even though it is beyond the scope of this RFA, we are very enthusiastic that the identified lead candidate will be taken into IND-enabling studies with financial support from Rempex-MedCo. Significance: Our innovative proposal will develop much-needed safer and more efficacious polymyxins to counteract the current global health crisis caused by Gram-negative ‘superbugs’.