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

基本信息

批准号：
10544529
负责人：
Jose L. Lopez-Ribot
金额：
$ 44.44万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

项目摘要

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主要威胁受损的患者。机会性的致病真菌念珠菌，曲霉和加密赛属。是最常见的霉菌性病因剂；但是其他酵母和霉菌引起的感染也在随着现代医学的进步，延长寿命的增长会越来越容易受到攻击和脆弱患者。但是，由于一个，真菌最近被称为“隐藏的杀手/被忽视的流行病” 缺乏对真菌疾病的伴随公众意识。有限的抗真菌剂的武器库有助于与真菌感染相关的高发病率和死亡率的高度高。真菌是真核生物，可以探索抗真菌药物开发的选择性靶标的很少。结果，抗真菌武器非常短，主要限于三类：多烯，叠氮和棘突。但是，高毒性和抵抗的出现是其临床使用的有限因素。做更糟糕的是，一些最麻烦的新兴真菌病原体完全落在这些当前抗真菌剂的活性谱。此外，大多数药物中的抗真菌管道公司本质上是干燥的。为了克服这一巨大挑战，当前的提案使用了高效的包括筛选重新利用库以识别具有新型抗真菌活性的化合物的方法其次是通过评估其在鼠模型中的活动来推进主要命中化合物的发展真菌感染，总体上关注抗性感染。 R21阶段的主要目标是：i）对Calibr的重框化学库进行大规模筛选，以识别具有的高价值化合物针对白色念珠菌生物膜的新型抗真菌活性和抗多药的念珠菌，新兴的病原体和增加的医院威胁，ii）确认抗真菌活性并确定抗真菌作用的抗真菌作用光谱。实现了设定的过渡里程碑选择有限数量的承诺线索，R33阶段的具体目的是：i）表征许多与真菌感染的临床动物模型中铅化合物的体内活性在实验室内完全建立的，ii）进一步表征铅化合物通过对扩展的真菌种类的临床分离株进行测试来测试。感兴趣，并与当前现有抗真菌抗体结合进行测试其体外活性。完全与拟议研究相关的强大翻译动力，以及组装的调查人员团队从医学上的基础上覆盖了基本的临床方面，应该最大化成功机会并允许加速新的抗真菌药物的发展，为此有紧迫而艰难的需求。