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

真菌感染构成了对不断扩大的免疫和医学领域的主要威胁 有危险的病人。条件致病真菌念珠菌、曲霉和隐球菌属。是 真菌病最常见的病原体；但由其他酵母菌和霉菌引起的感染仍在继续 随着现代医学的进步延长生命，这种疾病的发病率上升，导致越来越容易受到影响和脆弱 病人。然而，真菌最近被称为“隐藏的杀手/被忽视的流行病”，因为 缺乏伴随而来的公众对真菌病的认识。有限的抗真菌药物军火库有助于 与真菌感染相关的令人无法接受的高发病率和死亡率。真菌是真核生物，而且 可用于抗真菌药物开发的选择性靶点很少。因此， 抗真菌药物非常缺乏，主要限于三类：多烯类、氮唑类和棘球菌素类。 然而，高毒性和耐药性的出现限制了它们的临床应用。使 更糟糕的是，一些最麻烦的新出现的真菌病原体完全落在 这些当前抗真菌药物的活性光谱。此外，大多数制药公司的抗真菌管道 公司基本上是枯竭的。为了克服这一艰巨的挑战，目前的提案使用了一种高效的 筛选重组文库以鉴定具有新抗真菌活性的化合物的方法 其次是通过评估其在小鼠模型中的活性来促进领先HIT化合物的开发 真菌感染，总体重点是耐药感染。R21阶段的主要目标是：i) 对CALIBR重组化学文库进行大规模筛选，以鉴定具有高价值的化合物 抗白色念珠菌生物被膜和耐多药金黄色念珠菌的新活性 新出现的病原体和日益增加的医院威胁，以及ii)确认抗真菌活性并确定 初步筛选的HITS抗真菌作用谱。在实现设定的过渡里程碑之后 选择有限数量的有希望的线索，R33阶段的具体目标将是：i)表征 几种临床相关的真菌感染动物模型中先导化合物的体内活性 在实验室内完全建立的，以及ii)进一步表征其体外抗真菌活性 主要化合物通过测试它们与扩大数量的真菌种类的临床分离物 兴趣，以及测试它们的体外活性与现有的抗真菌药物相结合。总而言之 与拟议的研究相关的强大的翻译动力，以及 涵盖从基础到临床的医学真菌学的研究团队应该 最大限度地增加成功的机会，并允许加速开发新的抗真菌药物，为此 这是一种迫切而迫切的需求。

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.