How is Cryptococcus resistant ot echinocandins?

隐球菌如何对棘白菌素产生耐药性？

• 批准号: 6802271
• 负责人: Claude P Selitrennikoff
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802271
• 关键词: Cryptococcus neoformans; antifungal agents; drug resistance; enzyme inhibitors; glycosyltransferase; membrane transport proteins; microorganism culture; protein degradation

DESCRIPTION (provided by applicant): Cryptococcus neoformans is an encapsulated pathogenic yeast that causes disease in humans and other animals. Currently, the majority of human patients with cryptococcosis have diseases or treatments that cause suppression of cell-mediated immunity. During the last 20 years, there has been a dramatic increase in the incidence of cryptococcosis that mirrors the increase in HIV infections. AIDS patients are exquisitely vulnerable to opportunistic fungal infections. It has been estimated that 7-10% of patients with AIDS will contract cryptococcosis, and if left untreated, the disease is fatal. It is a leading cause of death in immunocompromised patients. Caspofungin, a new echinocandin (1,3)beta-glucan synthase inhibitor, is effective against many species of fungi and is well tolerated, safe, and effective; in contrast to the azoles, it is fungicidal and would be extremely useful in the treatment of primary cryptococcosis. However, its use to treat C. neoformans infections is precluded since the organism is resistant to caspofungin both in vitro and in vivo. This result is puzzling given that the gene encoding (1,3)beta-glucan synthase is essential for C. neoformans growth. The reason(s) for resistance has not been determined, but is likely to involve one of the following: 1. The target itself ([1,3]beta-glucan synthase) is resistant to caspofungin; 2. Caspofungin is transported out of the cell by, for example, ABC transporters; or 3. Caspofungin is degraded either extra- and/or intra-cellularly. In this R21 proposal, we will determine the mechanism of resistance of C. neoformans to echinocandins with the goal of developing a series of hypotheses that can be tested in an R01. The eventual goal of that work will be to develop a strategy to circumvent resistance, for example, the design of a caspofungin derivative that is effective against C. neoformans. We propose three specific aims: One: Determine the in vitro resistance of C. neoformans (1,3)beta-glucan synthase activity to caspofungin. Two: Determine the involvement of ABC transporters in caspofungin resistance. Three: Determine whether caspofungin is degraded by C. neoformans. At the conclusion of these preliminary studies, we anticipate that we will have determined which of the three resistance mechanisms is the most important for C. neoformans resistance to glucan synthase inhibitors.

描述（由申请人提供）： Neoformans是一种封装的致病酵母菌，可引起人类和其他动物的疾病。目前，大多数隐球菌病患者患有疾病或治疗，导致细胞介导的免疫力抑制。在过去的20年中，隐球菌病的发病率显着增加，反映了HIV感染的增加。艾滋病患者非常容易受到机会主义真菌感染的影响。据估计，有7-10％的艾滋病患者会收缩隐球菌病，如果未治疗，这种疾病是致命的。这是免疫功能低下的患者死亡的主要原因。 Caspofungin是一种新的echinocandin（1,3）β-葡聚糖合酶抑制剂，对许多真菌有效，并且耐受性良好，安全和有效。与硫唑相反，它是杀菌性的，在治疗原发性隐球菌病方面非常有用。然而，由于生物在体外和体内都具有抗性，因此它用于治疗新生虫感染。考虑到编码（1,3）β-葡聚糖合酶的基因对新梭菌的生长至关重要，因此这一结果令人困惑。抗电阻的原因尚未确定，但可能涉及以下一个：1。目标本身（[1,3]β-葡聚糖合酶）对Caspofungin具有抗性； 2。Caspofungin由例如ABC转运蛋白将其传输出细胞；或3。caspofungin脱落外部和/或细胞内降解。在此R21提案中，我们将确定新甲状腺梭菌对echinocandins的抗性机制，其目的是开发一系列可以在R01中检验的假设。这项工作的最终目标将是制定一种规避抵抗力的策略，例如，caspofungin衍生物的设计有效，该衍生物是针对Neoformans的有效的。我们提出了三个特定的目的：一：确定Neoformans（1,3）β-葡聚糖合酶活性对Caspofungin的体外耐药性。二：确定ABC转运蛋白参与Caspofungin电阻。三：确定caspofungin是否被梭菌新生虫降解。在这些初步研究的结论中，我们预计我们将确定三种抗性机制中的哪种对于新近甲状腺梭菌对葡萄糖合酶抑制剂的耐药性最重要。