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: 10584574
• 负责人: David R Andes
• 金额: $ 71万
• 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/10584574
• 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; Multiple Fungal Drug Resistance; Mus; Mycoses; Natural Products; Natural Products Chemistry; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Predisposition; Production; Property; Public Health; Rattus; Regimen; Research; Resistance; Resources; Safety; Series; Solubility; Source; Technology; Therapeutic; Therapeutic Index; Toxic effect; Wisconsin; Work; analog; antimicrobial; clinical development; clinically relevant; 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泛耐药真菌病原体的出现， 免疫功能低下的患者人数不断增加强调这种紧迫性的是， 耳念珠菌，对所有三种可用的抗真菌药物都有耐药性。细菌天然产物 已经成为抗感染药物包括抗真菌药物的重要来源。我们利用新的资源， 从海洋无脊椎动物微生物组收获细菌以产生天然产物筛选文库， 确定了turbinmicin，一种新的抗真菌药物靶向多药耐药（MDR）真菌病原体。涡轮霉素 对多种MDR-真菌病原体显示出有效的体外和体内功效，显示出宽的安全性指数， 并通过真菌特异性作用模式发挥作用，靶向囊泡运输途径。我们 随后合成turbinmicin类似物以调节包括溶解性的药物性质。 基于我们有希望的结果，我们的前提是，turbinmicin类似物代表了下一代安全的 和针对耐药真菌感染的有效抗真菌剂。在这个项目中，威斯康星州药物 发现和开发中心将使用先导优化开发turbinmicin，一种新的天然药物 新一代广谱无毒抗真菌药的代表产品。其宗旨是 重点关注有效性（具体目标1）、安全性（具体目标2）和生产/配方（具体目标3）。我们 将三个目标中的每一个分为两个连续的阶段。第1阶段将确定最有前途的铅类似物 基于功效、安全性和溶解性筛选。第2阶段将描述IND使能PK/PD疗效， 在已建立的小鼠模型和大鼠模型中的安全性。 影响：由于对新出现的泛耐药真菌病原体没有有效的治疗方法，我们的工作填补了 关键的未满足的需求。我们的研究将为临床开发一种新的 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的、尖端的 技术，以测试turbinmicin系列化合物的有效性和安全性，并优化药物生产。 这项研究将在杰出的环境中进行，由一个有凝聚力的PI和行业合作伙伴小组， 在临床前和临床抗菌药理学和天然产物方面具有互补的专业知识 化学.