How is Cryptococcus resistant ot echinocandins?

描述（由申请人提供）： 新型隐球菌是一种包囊致病性酵母，可引起人类和其他动物的疾病。目前，大多数患有隐球菌病的人类患者患有引起细胞介导的免疫抑制的疾病或治疗。在过去20年中，隐球菌病的发病率急剧增加，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，如果不及时治疗，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。卡泊芬净是一种新的棘白菌素（1，3）β-葡聚糖合成酶抑制剂，对许多种真菌有效，耐受性好，安全有效;与唑类药物相比，它具有杀真菌作用，在治疗原发性隐球菌病方面非常有用。然而，其用于治疗C.由于该生物体在体外和体内均对卡泊芬净具有抗性，因此排除了新生菌感染。这一结果令人困惑，因为编码（1，3）β-葡聚糖合酶的基因是C.新生儿的成长耐药原因尚未确定，但可能涉及以下原因之一：1.靶点本身（[1，3] β-葡聚糖合酶）对卡泊芬净具有抗性; 2.卡泊芬净通过例如ABC转运蛋白转运出细胞;或3.卡泊芬净在细胞外和/或细胞内降解。在这个R21方案中，我们将确定C.从新生动物到棘白菌素，目的是开发一系列可以在R 01中测试的假设。这项工作的最终目标将是开发一种策略来规避耐药性，例如，设计一种有效对抗C。新人类我们提出了三个具体的目标：一是确定体外耐药性。新型（1，3）β-葡聚糖合成酶活性对卡泊芬净的影响。第二：确定ABC转运蛋白参与卡泊芬净耐药。第三：确定卡泊芬净是否被C.新人类在这些初步研究的结论，我们预计，我们将确定这三个耐药机制是最重要的C。新生儿对葡聚糖合成酶抑制剂的耐药性。

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.