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

基本信息

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
项目类别：
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

项目摘要

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人类健康的泛耐药真菌病原体的出现免疫功能低下的患者群体不断增长。最近全球蔓延的疫情凸显了这一紧迫性耳念珠菌，对所有三种可用的抗真菌药物均具有耐药性。来自细菌的天然产物已成为抗感染药物（包括抗真菌药物）的重要来源。我们利用了新的资源从海洋无脊椎动物微生物组中收获的细菌，用于生成天然产物筛选库和鉴定出 turbinmicin，一种针对多重耐药 (MDR) 真菌病原体的新型抗真菌药物。土宾米星对多种 MDR 真菌病原体表现出强大的体外和体内功效，表现出广泛的安全指数，并通过真菌特异性的作用模式发挥作用，针对囊泡运输途径。我们随后合成了turbinmicin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，turbinmicin 类似物代表了下一代安全药物以及针对耐药真菌感染的有效抗真菌药物。在这个项目中，威斯康星州药物发现和开发中心将利用先导物优化来开发 turbinmicin，一种新型天然药物新型广谱、无毒抗真菌药物的代表产品。目标是重点关注功效（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目标分为两个连续的阶段。第一阶段将确定最有前途的领先类似物基于功效、安全性和溶解度筛选。第二阶段将描述支持 IND 的 PK/PD 功效和分别在已建立的小鼠模型和大鼠模型中的安全性。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，我们的工作填补了未满足的关键需求。我们的研究将为新药的临床开发提供多个支持 IND 的数据集针对高威胁耐药真菌的一类抗真菌药物。这些调查使用了互补的、尖端的测试Turbinmicin化合物系列的有效性和安全性并优化药物生产的技术。该研究将由 PI 和行业合作伙伴组成的有凝聚力的团队在出色的环境中进行，具有临床前和临床抗菌药理学和天然产物方面的互补专业知识化学。