High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris

疟疾药物的高通量筛选帮助化学库鉴定新型耳念珠菌抑制剂

• 批准号: 10383652
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383652
• 关键词: Academia; Amphotericin B; Antibiotic Resistance; Antifungal Agents; Antifungal Therapy; Awareness; Azoles; Biological; Biological Assay; Candida; Candida albicans; Candida auris; Candidiasis; Cell Line; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clinic; Clinical; Collection; Data; Development; Disease; Disease Outbreaks; Dose; Epidemic; Etiology; Eukaryota; Fluconazole; Fluconazole resistance; Fungal Drug Resistance; Generations; Growth; Health care facility; Human; Immune; In Vitro; Infection; Laboratories; Libraries; Malaria; Medical; Medical Research; Medicine; Micafungin; Modeling; Modern Medicine; Molds; Multi-Drug Resistance; Mycoses; National Institute of Allergy and Infectious Disease; Nature; Nonprofit Organizations; Nosocomial Infections; Nursing Homes; Parasitology; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Polyenes; Primary carcinoma of the liver cells; Property; Resistance; Resistance development; Safety; Strategic Planning; Structure; Toxic effect; United States National Institutes of Health; Yeasts; base; combat; design; drug development; emerging pathogen; experimental study; fungus; health care settings; high throughput screening; in vitro activity; in vitro testing; inhibitor; interest; mortality; neglect; novel; novel strategies; novel therapeutics; pathogen; programs; public-private partnership; response; small molecule; small molecule libraries; trend

Candida species represent the most frequent etiological agents of opportunistic fungal invasive infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach by establishing a novel partnership between academia (our laboratory) and a non-for profit organization (Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and safety/toxicity properties.

念珠菌物种代表了机会真菌侵入性最频繁的病因学剂 现在的免疫和医学促进性患者以及念珠菌病的范围不断扩展的感染 代表了全世界第三到四分之一最常见的医院感染 死亡率为30-60％，在过去的三十年中，令人震惊的是保持不变。最多 最近，念珠菌已经成为全球多药的机会真菌，包括 美国，具有显着的能力，可以轻松地在住院的患者和护士家居居民之间传播 导致医疗机构的重大爆发。根据疾病控制中心的数据和 预防（CDC），美国90％的Auris菌株对氟康唑具有抗性，30％是 对两性霉素B具有抗性，而5％对echinocandins具有抗性。那是一些事实 C. Auris对所有三种主要类别使用的临床抗真菌药物的泛抗性是 特别关心。确实，在最近发布的美国抗生素抗性威胁中 CDC将C. Auris指定为仅有的5种“紧急威胁”，需要迅速而积极的行动，因为 人们严重担心多种和泛氧化梭菌分离株将传播并变得普遍，并且 在未来的几年中，通常是不可治疗的。那，需要开发新疗法。 针对这种新兴的病原体。为了克服这一巨大挑战，我们提出了一种高效的方法 通过建立学术界（我们的实验室）与非盈利组织之间的新型伙伴关系 （疟疾风险药物，MMV），以进行MMV的高吞吐量筛查（HTS） 化学文库中含有180,000个小分子化合物，可识别新型化合物的高价值化合物 抗真菌活性针对Auris。尽管类似的方法对寄生虫有重大影响 字段，这些MMV的库从未被筛选为抗真菌活动。为此，我们提出了 以下内容：i）执行MMV化学库的HTS，以识别新型的高价值化合物 针对Auris的抗真菌活性，我们最近将使用基于384孔微量滴定板的模型 在我们的实验室中开发，以筛选MMV的“命中生成”（140K化合物）和“多样性”（40k 化合物）化学文库，以鉴定奥氏梭菌生长的抑制剂； ii）表征 通过进行一系列体外测试来进一步建立其抗真菌活性和 安全/毒性特性。

项目成果

High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms.

• DOI: 10.3390/jof9090879
• 发表时间: 2023-08-27
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Ajetunmobi OH;Wall G;Vidal Bonifacio B;Martinez Delgado LA;Chaturvedi AK;Najvar LK;Wormley FL Jr;Patterson HP;Wiederhold NP;Patterson TF;Lopez-Ribot JL
• 通讯作者: Lopez-Ribot JL