Screening a Target-Based Repurposing Library for Activity against Fungal Pathogens and Subsequent Preclinical Development of Leading Candidates

筛选基于靶点的再利用文库的抗真菌病原体活性以及主要候选药物的后续临床前开发

• 批准号: 10320258
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 44.35万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320258
• 关键词: Advanced Development; Amphotericin B; Animal Model; Antibiotic Resistance; Antifungal Agents; Antifungal Therapy; Aspergillosis; Aspergillus; Awareness; Azoles; Candida; Candida albicans; Candida auris; Candidiasis; Centers for Disease Control and Prevention (U.S.); Clinical; Collection; Cryptococcosis; Cryptococcus; Development; Disease; Dose; Epidemic; Etiology; Eukaryota; Fluconazole; Geography; Goals; Growth; Human; Immune; In Vitro; Infection; Knowledge; Laboratories; Lead; Libraries; Medical; Medical Research; Micafungin; Microbial Biofilms; Modeling; Modern Medicine; Molds; Morbidity - disease rate; Multi-Drug Resistance; Mycoses; National Institute of Allergy and Infectious Disease; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polyenes; Property; Research Personnel; Resistance; Safety; Strategic Planning; Testing; The science of Mycology; Toxic effect; United States National Institutes of Health; Yeasts; base; clinically relevant; drug development; emerging pathogen; experimental study; falls; fungus; in vitro activity; in vivo; inhibitor/antagonist; interest; mortality; mouse model; neglect; novel; novel therapeutics; pathogenic fungus; preclinical development; preclinical study; programs; response; screening; small molecule libraries; success

Fungal infections constitute a major threat to an ever expanding spectrum of immune- and medically- compromised patients. The opportunistic pathogenic fungi Candida, Aspergillus and Cryptococcus spp. are among the most common etiologic agents of mycoses; but infections caused by other yeasts and moulds are on the rise as advances in modern medicine prolong lives resulting in increasingly susceptible and vulnerable patients. However, fungi have recently been referred to as the “hidden killers/the neglected epidemic” due to a lack of concomitant public awareness in fungal disease. The limited arsenal of antifungal agents contributes to the unacceptably high morbidity and mortality rates associated with fungal infections. Fungi are eukaryotes, and there is a paucity of selective targets that can be exploited for antifungal drug development. As a consequence, the antifungal arsenal is exceedingly short, mostly limited to three classes: polyenes, azoles and echinocandins. However, high toxicity and the emergence of resistance are limited factors for their clinical usage. To make matters even worse, some of the most troublesome emerging fungal pathogens fall completely outside of the spectrum of activity of these current antifungals. Moreover, the antifungal pipeline in most pharmaceutical companies is essentially dry. To conquer this formidable challenge the current proposal uses a highly efficient approach consisting of screening a repurposing library to identify compounds with novel antifungal activity followed by advancing the development of the leading hit compounds by assessing their activity in murine models of fungal infections, with an overall focus on resistant infections. The main objectives for the R21 Phase are: i) to conduct a large-scale screening of Calibr’s ReFRAME chemical library to identify high value compounds with novel antifungal activity against Candida albicans biofilms and against multidrug resistant Candida auris, an emerging pathogen and increasing nosocomial threat, and ii) to confirm the antifungal activity and determine the antifungal spectrum of action of hits from primary screening. Upon achieving the set transitional milestones for selection of a limited number of promising leads, the specific aims for the R33 Phase will be: i) to characterize the in vivo activity of the leading compounds in a number of clinically-relevant animal models of fungal infection that are fully established within the laboratories, and ii) to further characterize the in vitro antifungal activity of the leading compounds by testing them against an expanded number of clinical isolates of fungal species of interest, as well as testing their in vitro activity in combination with current existing antifungals. Altogether the strong translational impetus associated with the proposed studies, together with the complementary expertise of the assembled team of investigators covering from basic to clinical aspects of Medically Mycology, should maximize the chances for success and allow for accelerated development of new antifungal drugs, for which there is an urgent and dire need.

真菌感染对不断扩大的免疫和医学范围构成了重大威胁， 妥协的病人条件致病真菌念珠菌属、曲霉属和隐球菌属。是 是真菌病最常见的病原体之一，但由其他酵母菌和霉菌引起的感染也在增加。 随着现代医学进步延长了生命， 患者然而，真菌最近被称为“隐藏的杀手/被忽视的流行病”，因为 公众对真菌病缺乏相应的认识。有限的抗真菌药物有助于 与真菌感染相关的不可接受的高发病率和死亡率。真菌是真核生物， 可用于抗真菌药物开发的选择性靶点很少。因此，在这方面， 抗真菌药物库非常短，主要限于三类：多烯、唑类和棘白菌素。 然而，高毒性和耐药性的出现限制了其临床应用。使 更糟糕的是，一些最麻烦的新出现的真菌病原体完全不属于 这些当前抗真菌药的活性谱。此外，大多数制药公司的抗真菌药物管道 公司基本上是干的。为了克服这一艰巨的挑战，目前的建议使用了一种高效的 一种方法，包括筛选一个再利用的库，以确定具有新的抗真菌活性的化合物 随后通过评估其在小鼠模型中的活性来推进主要命中化合物的开发 真菌感染，总体重点是耐药性感染。R21阶段的主要目标是：i） 对Calibr的ReFRAME化学库进行大规模筛选，以识别高价值化合物， 本发明提供了一种新的抗白念珠菌生物膜和抗多药耐药耳念珠菌的抗真菌活性， 新出现的病原体和增加的医院威胁，和ii）确认抗真菌活性并确定 抗真菌作用谱的初步筛选命中。在实现既定的过渡里程碑后， 选择数量有限的有前途的电极导线，R33阶段的具体目标将是：i）表征 先导化合物在许多临床相关的真菌感染动物模型中的体内活性 在实验室内完全建立，和ii）进一步表征的体外抗真菌活性 通过测试它们对扩大数量的临床分离的真菌物种的领先的化合物， 感兴趣，以及测试它们与当前现有的抗真菌剂组合的体外活性。总共 与拟议研究相关的强大翻译动力，以及 由医学真菌学的基础到临床方面的研究人员组成的研究小组，应 最大限度地提高成功的机会，并允许加速开发新的抗真菌药物， 有一种迫切和迫切的需要。