In vivo Core

项目摘要 大型制药公司的抗菌素创新放缓，而抗菌素耐药性感染的流行激增，威胁着公众健康。威斯康星州抗菌药的首要目标 药物发现和开发中心正在制定治疗对策，以应对抗菌素 抵抗危机。根据我们的初步数据，我们假设共生的天然产物勘探 使用互补的尖端方法的环境将为发现新的 针对耐药感染的抗菌药。该中心提出了创新的概念和技术 克服传统抗微生物药物发现平台中确定的关键瓶颈的进展。这个 这一努力的成功取决于预测共生体抗菌效果的能力 患者体内的天然产品。体内核心将评估体内微生物学效果，哺乳动物 新型天然产物支架的安全性、药动学和药效学研究 项目(1，2，3)在中心。Core使用临床相关的小鼠感染模型，每个模型 目标、耐药病原体--革兰氏阴性细菌和真菌。这些核心活动的结果 将预测哪些在体外对耐药病原体具有良好活性的化合物可能 一种临床有用的抗菌药的进展。核心服务还将提供数据来回答 问：我们的三个CETR项目采用的哪种新的发现方法最能提供线索 抗菌化合物。阐明最佳发现策略将产生变革性和持续性的 对新药开发的影响。

Project Summary Antimicrobial innovation by larger pharmaceutical companies has slowed while an epidemic of antimicrobialresistant infections surges, threatening the public health. The overarching goal of the Wisconsin Antimicrobial Drug Discovery and Development Center is to develop therapeutic countermeasures to tackle the antimicrobial resistance crisis. Based upon our preliminary data, we hypothesize that natural product exploration of symbiotic environments using complementary cutting-edge approaches will provide a new paradigm for discovery of novel antimicrobials targeting drug resistant infections. The Center proposes innovative conceptual and technical advances to overcome critical bottlenecks identified in traditional antimicrobial drug discovery platforms. The success of this endeavor is dependent upon the ability to predict antimicrobial effectiveness of the symbiotic natural products in patients. The In vivo Core will assess the in vivo microbiologic effectiveness, mammalian safety, pharmacokinetics and pharmacodynamics of promising novel natural product scaffolds from each Project (1, 2, 3) in the Center. The Core uses clinically relevant murine infection models with each of the target, drug-resistant pathogens – Gram negative bacteria and fungi. The results from these Core activities will predict which compounds with promising in vitro activity against drug-resistant pathogens are likely to progress to a clinically useful antimicrobial drug. The core services will also provide data that answer the question: which of the novel discovery approaches employed by our three CETR projects best delivers lead antimicrobial compounds. Elucidation of optimal discovery strategies will yield a transformative and sustained impact on the development of new drugs.