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.

侵入性真菌感染是全球发病率和死亡率的主要原因，约为1.4 每年有百万人死亡。念珠菌属的酵母菌引起的血液真菌感染是 与高死亡率相关（45-75％），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，早产婴儿和艾滋病患者。 echinocandin 药物是在2001年首次批准用于临床使用的，是我们有限的抗真菌药物武器的重要组成部分 并且对念珠菌物种具有广泛的活跃。这些药物阻止真菌聚糖合酶，一种酶 催化真菌细胞壁的主要结构成分β-1,3葡聚糖的生物合成。 echinocandin 由于基因的“热点” FKS1和FKS2的“热点”区域的突变，导致临床失败导致临床失败的抗性， 它编码β-1,3葡萄糖合酶亚基。而大多数念珠菌属。表现出一贯的低 chinocandin耐药性的频率（1-3％），念珠菌是一个例外，有一些移植 报告的中心报告了Glabrata C. echinocandin耐药率为10-15％。 eChinocandin的阻力总是出现 在治疗过程中，预计会进一步增加，因为扩大的患者数量暴露于抗真菌中 预防性和棘手类药物成为通用的药物。此外，C。glabrata的发生率是 增加，现在是仅次于北美白色念珠菌的第二大普遍的真菌病原体 欧洲。那就是迫切需要更好地理解导致出现的因素 C. glabrata中的echinocandin耐药性。根据最近的研究，该提案围绕该假设的中心 由我们的实验室和其他人出版，抵抗的出现在两个阶段之前：宽容， 多种细胞因子在药物暴露期间稳定glabrata并逃脱，抗chinocandin耐药 FKS突变在耐药细胞中发展。我们建议确定对这两种造成的因素 通过以下完整方法阶段：（1）测试候选基因在药物耐受性中的作用 并在体外的体外发展抗性（逃脱），并在体内验证它们，（2）识别遗传 在我们广泛的glabrata临床分离株中，影响药物耐受性和逃脱的多态性 （〜1000个菌株）来自美国和全球的潜水员地理位置。对于每种方法， 我们将利用我们定义明确的体外测定法，最近开发了与临床相关的胃肠道 殖民化和腹腔内脓肿模型模仿人类的抗性出现。在一起，这些 方法将定义重要真菌病原体的基本生物学的关键特征，并确定 可以改善热成功并防止阻力发展的目标。此外， 理解确定临床C. glabrata菌株中的耐受性和耐药性将导致潜力 追踪高威胁菌株的分子流行病学的诊断暗杀。