Critical Factors Influencing Echinocandin Resistance in Candidaglabrata

影响光滑念珠菌棘白菌素耐药性的关键因素

• 批准号: 10451830
• 负责人: David S Perlin
• 金额: $ 71.06万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451830
• 关键词: Abscess; Accounting; Acquired Immunodeficiency Syndrome; Anabolism; Antifungal Agents; Biology; Blood Circulation; Cancer Patient; Candida; Candida albicans; Candida glabrata; Candidate Disease Gene; Cells; Cellular Structures; Cessation of life; Clinical; Collection; Drug Exposure; Drug Tolerance; Enzymes; Europe; Exposure to; Failure; Frequencies; Fungal Components; Genes; Genetic Polymorphism; Geographic Locations; Glucans; Hot Spot; Human; Immunocompromised Host; In Vitro; Incidence; Individual; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mutation; Mycoses; North America; Patients; Pharmaceutical Preparations; Premature Infant; Prophylactic treatment; Publishing; Reporting; Resistance; Resistance development; Role; Testing; Therapeutic; Yeasts; base; clinically relevant; diagnostic assay; drug development; echinocandin resistance; gastrointestinal; glucan synthase; improved; in vitro Assay; in vivo; mortality; organ transplant recipient; pathogenic fungus; prevent; success; transplant centers

Invasive fungal infections are a major cause of global morbidity and mortality, accounting for nearly 1.4 million deaths a year. Bloodstream fungal infections, largely caused by yeasts of the Candida genus, are associated with high mortality rates (45-75%) and pose a serious threat to immunocompromised individuals, including cancer patients, organ transplant recipients, premature infants, and AIDS patients. The echinocandin drugs, first approved for clinical use in 2001, are an essential part of our limited antifungal drug armamentarium and are broadly active against Candida species. These drugs block fungal glucan synthase, an enzyme catalysing the biosynthesis of β-1,3 glucan, a major structural component of the fungal cell wall. Echinocandin resistance resulting in clinical failures arises due to mutations in the “hot spot” regions of genes FKS1 and FKS2, which encode β-1,3 glucans synthase subunits. While most Candida spp. have shown a consistently low frequency of echinocandin resistance (1-3%), Candida glabrata has been an exception, with some transplant centers reporting C. glabrata echinocandin resistance rates of 10-15%. Echinocandin resistance always arises during therapy and is expected to increase further, as expanding numbers of patients are exposed to antifungal prophylaxis and echinocandin class drugs become generic. Furthermore, C. glabrata incidence has been increasing and it now is the second most prevalent fungal pathogen after C. albicans in North America and Europe. Thus, there is an urgent need to better understand the factors that contribute to emergence of echinocandin resistance in C. glabrata. This proposal centers around the hypothesis, based on recent studies published by our lab and others, that emergence of resistance is preceded by two stages: tolerance, where multiple cellular factors stabilize C. glabrata during drug exposure, and escape, where echinocandin-resistant fks mutations develop in the drug-tolerant cells. We propose to identify factors contributing to both of these stages by the following complementary approaches: (1) testing the roles of candidate genes in drug tolerance and development of resistance (escape) in vitro and validating them in vivo, and (2) identifying genetic polymorphisms that influence drug tolerance and escape in our extensive collection of C. glabrata clinical isolates (~1000 strains) derived from diverse geographical locations in the U.S. and around the globe. For each approach, we will utilize our well-defined in vitro assays and recently developed clinically-relevant gastrointestinal colonization and intraabdominal abscess models that mimic resistance emergence in humans. Together, these approaches will define critical features of the underlying biology of an important fungal pathogen and identify targets that can improve therapeutic success and prevent development of resistance. Furthermore, understanding determinants of tolerance and resistance in clinical C. glabrata strains will lead to potential diagnostic assays to track the molecular epidemiology of high-threat strains.

侵袭性真菌感染是全球发病率和死亡率的主要原因，占全球发病率和死亡率的近 1.4 每年有数百万人死亡。血流真菌感染主要由念珠菌属酵母菌引起， 与高死亡率（45-75%）相关，并对免疫功能低下的个体构成严重威胁， 包括癌症患者、器官移植接受者、早产儿和艾滋病患者。棘白菌素 这些药物于 2001 年首次批准用于临床，是我们有限的抗真菌药物库的重要组成部分 对念珠菌属具有广泛活性。这些药物可阻断真菌葡聚糖合酶（一种酶） 催化β-1,3葡聚糖的生物合成，β-1,3葡聚糖是真菌细胞壁的主要结构成分。棘白菌素 由于 FKS1 和 FKS2 基因“热点”区域的突变而产生导致临床失败的耐药性， 编码β-1,3葡聚糖合酶亚基。虽然大多数念珠菌属。一直表现出低水平 棘白菌素耐药率（1-3%），光滑念珠菌是一个例外，有一些移植 中心报告光滑念珠菌棘白菌素耐药率为 10-15%。棘白菌素耐药性总是会出现 在治疗期间，随着越来越多的患者接触抗真菌药物，预计会进一步增加 预防和棘白菌素类药物成为通用药物。此外，光滑 C. glabrata 的发病率 增加，目前它是北美第二大流行的真菌病原体，仅次于白色念珠菌 欧洲。因此，迫切需要更好地了解导致这种现象出现的因素。 光滑念珠菌中的棘白菌素抗性。该提案以基于最近研究的假设为中心 我们的实验室和其他人发表的研究表明，耐药性的出现之前有两个阶段：耐受性，其中 多种细胞因子在药物暴露和逃逸过程中稳定光滑念珠菌，其中棘白菌素耐药 fks 突变在耐药细胞中发生。我们建议确定导致这两者的因素 通过以下补充方法分阶段进行：（1）测试候选基因在耐药性中的作用 和体外耐药性（逃逸）的发展并在体内验证它们，以及（2）识别遗传 在我们广泛收集的光滑念珠菌临床分离株中影响药物耐受性和逃逸的多态性 （约 1000 株）来自美国和全球不同的地理位置。对于每种方法， 我们将利用我们明确的体外测定和最近开发的临床相关胃肠道检测 模拟人类耐药性出现的定植和腹内脓肿模型。在一起，这些 方法将定义重要真菌病原体的基础生物学的关键特征，并确定 可以提高治疗成功率并防止耐药性发展的目标。此外， 了解临床光滑念珠菌菌株耐受性和耐药性的决定因素将带来潜在的结果 跟踪高威胁菌株的分子流行病学的诊断测定。