The glyoxylate cycle as a new target for antifungals

描述(申请人提供)：真菌导致多种疾病状态。最常见的例子是相对轻微的局部皮肤和粘膜感染，如脚气、阴道酵母菌感染和角化指甲感染。然而，不祥的是，真菌数量的增加会导致内脏受累的全身性疾病。这些已经成为严重的、危及生命的问题，对于宿主防御机制受损的患者来说，这些问题很难诊断，甚至更难治疗。 治疗真菌感染的部分困难，特别是在免疫功能低下的宿主中，是有限的抗真菌药物。目前可用的药物包括与真菌膜麦角甾醇形成络合物的多烯(如两性霉素B)、抑制麦角甾醇生物合成途径步骤的一些氮唑和烯丙胺、抑制核酸合成的氟胞嘧啶，以及(1，3)β-葡聚糖合成酶抑制剂Canidas。不幸的是，两性霉素B有许多急性和慢性不良反应。氟胞嘧啶的活性范围很窄，由于耐药真菌的发展，治疗失败的情况时有发生。唑类药物只具有抗真菌作用，对常用的唑类药物的耐药性正成为一个重要的临床问题。人们普遍认为，迫切需要具有不同于现有药物作用机制的新药。 申请者的长期目标是发现对乙醛循环中的酶起作用的新型抗真菌药物。乙醛酸循环在人类中是不存在的，它对真菌的致病性是必不可少的，并且是抗真菌药物开发的一条未被开发的途径。研究人员将通过两个目标实现这一目标：(1)分离和鉴定5至10种乙醛酸循环酶抑制剂，并确定它们对真菌细胞的效力和对人类细胞的毒性；(2)使用白色念珠菌小鼠模型确定两种最活跃的化合物的体内疗效。最终，这项工作将导致分离出治疗人类真菌疾病的新类化合物。申请者预测，由于人类没有乙醛酸循环，这些抑制剂将是安全有效的治疗药物。

DESCRIPTION (provided by applicant): Fungi cause a wide spectrum of disease states. The most common examples are relatively minor, localized infections of the skin and mucous membranes such as athlete's foot, vaginal yeast infections, and infections of keratinized nails. However, an ominously increasing number of fungi cause systemic disease with the involvement of internal organs. These have become serious and life-threatening problems that are very difficult to diagnose and even more challenging to treat in patients with impaired host-defense mechanisms. Part of the difficulty in treating fungal infections, especially in immunocompromised hosts, is the limited armamentarium of antifungal drugs. Currently-available drugs include polyenes (e.g., amphotericin B) that complex with fungal-membrane ergosterol, a number of azoles and allylamines that inhibit steps in the ergosterol biosynthetic pathway, flucytosine that inhibits nucleic acid synthesis, and Cancidas, a (1,3)beta-glucan synthase inhibitor. Unfortunately, amphotericin B has a number of acute and chronic adverse effects. Flucytosine has a narrow spectrum of activity and is plagued with treatment failures due to the development of resistant fungi. Azoles are only fungistatic and resistance to commonly-used azoles is becoming a significant clinical problem. There is general agreement that there is a critical and immediate need for novel drugs with mechanisms of action different from current drugs. The applicant's long-term goal is to discover novel antifungals that are active against enzymes of the glyoxylate cycle. The glyoxylate cycle, which is absent in humans, is essential for fungal pathogenicity and represents an unexploited pathway for the development of antifungal drugs. The investigators will accomplish this in Two Aims: (1) to isolate and identify 5 to10 inhibitors of the glyoxylate cycle enzymes and determine their potency against fungal cells and toxicity against human cells; (2) to determine the in vivo efficacy of two of the most active compounds using a Candida albicans murine model. Ultimately, this work will lead to the isolation of new classes of compounds for treatment of human fungal disease. The applicant predicts that, since humans do not have the glyoxylate cycle, the inhibitors will be safe and effective therapeutics.