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)： 新生隐球菌是一种被包裹的致病酵母菌，会在人类和其他动物中引起疾病。目前，大多数人类隐球菌病患者都有导致细胞免疫抑制的疾病或治疗。在过去的20年里，隐球菌病的发病率急剧增加，这反映了艾滋病毒感染的增加。艾滋病患者极易受到机会性真菌感染。据估计，7%-10%的艾滋病患者会感染隐球菌病，如果不治疗，这种疾病是致命的。它是免疫功能低下患者死亡的主要原因。卡泊芬净是一种新型棘球菌素(1，3)β-葡聚糖合成酶抑制剂，对多种真菌有效，耐受性好，安全有效；与氮唑类药物相比，它具有杀菌作用，在治疗原发隐球菌病方面非常有用。然而，由于卡泊芬净在体外和体内都对卡泊芬净具有抗药性，因此不能使用它来治疗新生梭菌感染。这一结果令人费解，因为编码(1，3)β-葡聚糖合成酶的基因对新生葡萄球菌的生长是必不可少的。产生抗药性的原因(S)尚未确定，但可能与以下因素之一有关：1.靶标([1，3]β-葡聚糖合成酶)本身对卡泊芬净具有抗药性；2.卡泊芬净由ABC转运蛋白转运出细胞外；或3.卡泊芬净在细胞外和/或细胞内降解。在这份R21提案中，我们将确定新生葡萄球菌对棘球菌素类药物的耐药性机制，目的是开发一系列可以在R01中测试的假说。这项工作的最终目标将是开发一种规避耐药性的策略，例如，设计一种对新生葡萄球菌有效的卡泊芬净衍生物。我们提出了三个特定的目标：一：确定新生葡萄球菌(1，3)β-葡聚糖合成酶对卡泊芬净的体外耐药性。第二：确定ABC转运蛋白在卡泊芬净耐药中的作用。三：确定卡泊芬净是否被新生芽孢杆菌降解。在这些初步研究的结论中，我们预计我们将确定三种耐药机制中哪一种是导致新生葡萄球菌对葡聚糖合成酶抑制剂耐药最重要的。