A Combination Therapy Approach to Treating Drug Resistant Fungal Infections

描述（由申请人提供）：迫切需要发现更有效的真菌感染治疗方案。由白色念珠菌引起的医院感染有50%的死亡率。结核病是器官移植受者以及患有癌症和自身免疫疾病的患者死亡的主要原因。在美国，每年治疗真菌感染的费用约为26亿美元，并且由于患有这些疾病的免疫功能低下患者的数量增加而增加。真菌对广泛使用的抗真菌药物（包括三唑类和棘白菌素类）的耐药性的出现进一步损害了有限的抗真菌治疗药物的疗效。许多体外和体内研究已经确定，抑制真菌蛋白钙调磷酸酶的分子与几种重要类别的抗真菌治疗剂（包括三唑和棘白菌素）具有高度协同作用。然而，利用真菌钙调磷酸酶作为治疗靶点的巨大挑战是与人钙调磷酸酶的结构相似性，并且人钙调磷酸酶的抑制引起严重的免疫抑制和毒性。通过利用最近开发的化学方法来产生各种FK506类似物，我们已经分离出一种分子，其具有与FK506相当或更高的抗真菌活性和可忽略的免疫抑制作用。当与常见的抗真菌药物组合时，该分子对耐药临床分离株具有优异的效力。在这些初步结果的鼓舞下，我们希望创建一个更大的FK 506类似物库，以发现无毒、高度抗真菌并与现有治疗药物协同的分子。我们的总体目标是开发一种有效的联合治疗方法，可用于耐药真菌感染。我们的目标是：目标1。FK506类似物的1000个成员聚焦文库的设计和合成。目标2.筛选和选择缺乏免疫抑制的文库。目标3.筛选和选择库的抗真菌作用时，与已建立的抗真菌药物。 公共卫生相关性：由于可用于治疗真菌引起的疾病的医疗设备有限，真菌感染是一个重大挑战。由白色念珠菌引起的医院感染有50%的死亡率。Ampronix提出了一种新的联合治疗方法，通过设计和合成非免疫抑制分子来抑制真菌钙调磷酸酶，从而治疗耐药性真菌感染，该分子可以与现有的抗真菌药物共同给药。

DESCRIPTION (provided by applicant): There is an urgent need to discover more effective therapeutic regimens for fungal infections. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Aspergillosis is a leading cause of death in organ transplant recipients, as well as patients suffering from cancer and auto-immune disorders. The annual cost of treating fungal infections is about $2.6 billion in the United States and is increasing due to the larger number of immunocompromised patients who suffer from these illnesses. The emergence of fungal drug resistance to widely used antifungals including triazoles and echinocandins further compromises the efficacy of the limited armamentarium of antifungal therapeutics. A number of in vitro and in vivo studies have established that molecules which inhibit the fungal protein, calcineurin, are highly synergistic with several important classes of antifungal therapeutics including triazoles and echinocandins. However, a great challenge with exploiting fungal calcineurin as a therapeutic target is the structural similarity to human calcineurin, and that inhibition of human calcineurin causes severe immunosuppression and toxicity. By exploiting recently developed chemistry to generate a variety of FK506 analogues, we have isolated a molecule which has equivalent or higher antifungal activity than FK506 and negligible immunosuppression. When combined with common antifungals, this molecule had excellent potency against drug resistant clinical isolates. Encouraged by these initial results, we wish to create a larger library of FK506 analogues in order to discover molecules that are non-toxic, highly antifungal, and synergistic with existing therapeutics. Our overall goal is to develop an effective combination therapy which can be applied to drug resistant fungal infections. Our aims are: Aim 1. Design and synthesis of a 1000 member focused library of FK506 analogues. Aim 2. Screen and select library for lack of immunosuppression. Aim 3. Screen and select library for antifungal effects when combined with established antifungal drugs. PUBLIC HEALTH RELEVANCE: Fungal infections represent a significant challenge due to the limited armamentarium available to treat diseases caused by fungi. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Amplyx proposes a new combination therapy approach to treating drug resistant fungal infections via the design and synthesis of non-immunosuppressive molecules to inhibit fungal calcineurin that can be co-administered with existing antifungals.