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

背景：世界正面临着一个巨大的和日益增长的威胁， 细菌“超级细菌”如果细菌继续对多种抗生素产生耐药性， 与此同时，抗生素管道继续干涸， 可能会给全球的医疗保健和社会带来灾难性的损失。众多医院 世界各地都经历了由多药耐药（MDR）引起的感染爆发 铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌。所有这些 病原体在IDSA的六种最优先危险细菌的“打击名单”上， 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，多粘菌素类药物的肾毒性阻碍了其临床应用 以及由于药代动力学限制而对肺部感染的疗效差。不幸的是， 最近已经报道了质粒携带的对多粘菌素的抗性。本质上， 耐药性意味着完全缺乏抗生素来治疗致命的感染， 被这些革兰氏阴性菌感染因此，迫切需要开发新的抗生素。 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年的系统多粘菌素药理学研究中， 该项目将采用我们的新的构效关系（SAR）和结构毒性 STR关系（STR）模型，以合理开发新的，更安全的多粘菌素样脂肽， 针对革兰氏阴性“超级细菌”，包括耐多粘菌素菌株。具体目标是： (1)利用我们完善的脂肽药物化学平台，设计、合成 并对约300种新型脂肽进行了抗MDR K的微生物学评价。 pneumoniae、铜绿假单胞菌和A.（2）进行主要候选人的选择 基于动物模型中的急性毒性、疗效和肾毒性， 临床分离株的扩展组。在完成目标2后，制备了先导候选脂肽和先导候选脂肽。 将选择备份进行进一步开发（具体目标4）。(3)为了阐明 我们的多粘菌素样脂肽的抗菌活性和肾毒性， 药理学和化学生物学。这些机制研究将改进我们的SAR/STR模型， 有利于IND申请;以及（4）开发IND使能的主要候选人（和后备） 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评价的研究 啮齿动物模型。特定目标4的结果也将提供基本的疗效和毒性 数据，以支持未来的IND赋能研究。尽管这超出了RFA的范围，但我们 非常热情地认为，已确定的主要候选人将被纳入IND赋能研究， 获得了Rempex MedCo的资金支持。意义：我们的创新提案将发展 急需更安全、更有效的多粘菌素，以应对当前的全球健康危机 是由革兰氏阴性菌“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 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’.