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

基于共生的涡轮霉素的发现，这是一种针对耐药真菌的安全且选择性的抗真菌药物

• 批准号: 10414553
• 负责人: David R Andes
• 金额: $ 77.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414553
• 关键词: Address; Animals; Anti-Infective Agents; Antifungal Agents; Aspergillosis; Bacteria; Candida auris; Candidiasis; Characteristics; Chemicals; Clinical; Column Chromatography; Crystallization; Data; Data Set; Dose; Drug Formulations; Drug Industry; Drug Targeting; Drug resistance; Environment; Exhibits; Formulation; Fungal Drug Resistance; Goals; Harvest; High Pressure Liquid Chromatography; Human; Immunocompromised Host; In Vitro; Infection; Investigation; Lead; Libraries; Marine Invertebrates; Measures; Modeling; Multi-Drug Resistance; Multiple Fungal Drug Resistance; Mus; Mycoses; Natural Products; Natural Products Chemistry; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Predisposition; Preparation; Production; Property; Public Health; Rattus; Regimen; Research; Resistance; Resources; Safety; Series; Solubility; Source; Technology; Therapeutic; Therapeutic Index; Toxic effect; Wisconsin; Work; analog; antimicrobial; base; clinical development; clinically relevant; cohesion; design; drug development; drug discovery; drug production; effective therapy; efficacy study; efficacy testing; fungus; genomic tools; improved; in vivo; indexing; industry partner; lead optimization; metabolomics; microbiome; mouse model; next generation; novel; pathogen; pathogenic fungus; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; safety study; screening; symbiont; trafficking

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.

需要新的抗真菌药物来解决威胁威胁的泛毒真菌病原体的出现 不断增长的免疫功能低下的患者人群。强调这种紧迫性是最近的全球传播 念珠菌Auris，对所有三个可用的抗真菌类别都有抵抗力。细菌的天然产品 曾是包括抗真菌物在内的抗感染物的重要来源。我们利用了新来源 从海洋无脊椎动物微生物中收获的细菌，以产生天然产品筛选文库和 鉴定出涡轮蛋白是一种新型的抗真菌靶向多药耐药（MDR）真菌病原体。涡轮激素 在体外和体内对多种MDR杂种病原体的有效疗效，表现出广泛的安全指数， 并通过真菌特异性的作用方式来瞄准囊泡运输途径。我们 随后合成涡轮素类似物来调节包括溶解度在内的药物特性。 基于我们有希望的结果，我们的前提是涡轮素类似物代表下一代安全 和有效的抗真菌靶向抗药性真菌感染。在这个项目中，威斯康星州毒品 发现与开发中心将使用铅优化来发展涡轮激素，这是一种新颖的自然 来自新的广谱和无毒抗真菌剂的产品代表。目的是 专注于疗效（特定目标1），安全性（特定目标2）和生产/配方（特定目标3）。我们 将三个目标分为两个顺序阶段。第1阶段将确定最有希望的铅类似物 基于功效，安全性和溶解度筛选。第2阶段将描绘出pk/pd的效力和 既定的鼠模型和大鼠模型的安全性。 影响：由于没有有效的新兴泛药物耐药真菌病原体的疗法，我们的工作填充了 关键的未满足需求。我们的研究将为新的数据集提供新的数据集 靶向高威胁药物的真菌的一类抗真菌。调查使用互补的尖端 测试涡轮素化合物系列的功效和安全性并优化药物生产的技术。 这项研究将由一个凝聚力的PI和行业合作伙伴组在杰出的环境中进行， 具有临床前和临床抗菌药理学和天然产品方面的互补专业知识 化学。