Symbiotic-based discovery of turbinmicin, a safe and selective antifungal against resistant fungi

需要新的抗真菌药物来解决泛耐药真菌病原体的出现，这些病原体威胁着 不断增长的免疫功能受损的患者群体。突显这种紧迫性的是最近在全球范围内传播的 金黄色念珠菌，它对所有三种可用的抗真菌类别都具有耐药性。细菌天然产物 已经成为包括抗真菌药物在内的抗感染药物的重要来源。我们利用新的资源 从海洋无脊椎动物微生物群中采集细菌以产生天然产物筛选文库和 鉴定了一种针对多药耐药(MDR)真菌病原体的新型抗真菌药物--图宾米星。特比米星 对多种耐多药真菌病原体表现出强大的体外和体内药效，表现出广泛的安全指数， 并通过真菌特有的作用模式发挥作用，靶向囊泡运输途径。我们 随后合成了图比米星类似物来调节包括溶解度在内的药学性质。 基于我们令人振奋的结果，我们的前提是Turbinmicin类似物代表下一代安全的 并针对耐药真菌感染进行有效的抗真菌治疗。在这个项目中，威斯康星州的药物 发现和开发中心将使用领先优化技术开发新型天然药物Turbinmicin 产品代表来自新型广谱无毒抗真菌药。我们的目标是 侧重于疗效(具体目标1)、安全性(具体目标2)和生产/制剂(具体目标3)。我们 将三个目标中的每一个分成两个连续的阶段。阶段1将确定最有希望的铅类似物 基于有效性、安全性和溶解性筛选。阶段2将描述支持IND的PK/PD有效性和 在已建立的小鼠模型和大鼠模型中分别是安全的。 影响：由于目前还没有针对新出现的泛耐药真菌病原体的有效疗法，我们的工作填补了 严重的未得到满足的需求。我们的研究将为临床开发新的IND提供几个数据集 一类针对高威胁耐药真菌的抗真菌药物。这些调查使用了互补性的、尖端的 测试特比米星系列化合物的有效性和安全性，并优化药物生产的技术。 这项研究将由一群具有凝聚力的个人投资机构和行业合作伙伴在出色的环境中进行， 在临床前和临床抗菌药物药理和天然产品方面具有互补的专业知识 化学反应。

New antifungal drugs are needed to address the emergence of pan-drug resistant fungal pathogens that threaten a growing immunocompromised patient population. Underscoring this urgency is the recent global spread of Candida auris, which is resistant to all three of the available antifungal classes. Natural products from bacteria have served as an important source of anti-infectives, including antifungals. We leveraged new sources of bacteria harvested from marine invertebrate microbiomes to generate natural product screening libraries and identified turbinmicin, a novel antifungal targeting multidrug resistant (MDR) fungal pathogens. Turbinmicin displays potent in vitro and in vivo efficacy toward multiple MDR-fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting the vesicular trafficking pathway. We subsequently synthesized turbinmicin analogs to modulate the pharmaceutical properties including solubility. Based on our promising results, our premise is that turbinmicin analogs represent the next generation of safe and effective antifungal targeting drug resistant fungal infections. In this project, the Wisconsin Drug Discovery and Development Center will use lead optimization to develop turbinmicin, a novel natural product representative from a new class of broad-spectrum and non-toxic antifungals. The aims are focused on efficacy (specific aim 1), safety (specific aim 2), and production/formulation (specific aim 3). We divide each of the three aims into two sequential Stages. Stage 1 will identify the most promising lead analog based upon efficacy, safety, and solubility screens. Stage 2 will delineate IND-enabling PK/PD efficacy and safety in established murine models and rat models, respectively. Impact: As there are no effective therapies for emerging pan-drug resistant fungal pathogens, our work fills a critical unmet need. Our studies will provide several IND-enabling datasets for clinical development of a new class of antifungal targeting high threat drug-resistant fungi. The investigations use complementary, cutting-edge technologies to test the efficacy and safety of the turbinmicin compound series, and optimize drug production. The research will be performed in outstanding environments by a cohesive group of PIs and industry partners, with complementary expertise in preclinical and clinical antimicrobial pharmacology and natural product chemistry.