The glyoxylate cycle as a new target for antifungals

乙醛酸循环作为抗真菌药物的新靶点

• 批准号: 6579674
• 负责人: Claude P Selitrennikoff
• 金额: $ 10万
• 依托单位: MYCOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579674
• 关键词: Candida albicans; antifungal agents; candidiasis; dicarboxylate; drug design /synthesis /production; drug discovery /isolation; laboratory mouse; oxalates; short chain fatty acid

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.

描述（由申请人提供）：真菌引起广泛的疾病状态。 最常见的例子是皮肤和粘膜的相对较小的局部感染，如运动员的脚，阴道酵母菌感染和角化指甲的感染。 然而，越来越多的真菌引起全身性疾病，累及内脏器官。 这些已经成为严重的和危及生命的问题，非常难以诊断，甚至更具挑战性的治疗与受损的宿主防御机制的患者。 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，是抗真菌药物的有限设备。 目前可用的药物包括多烯（例如，与真菌膜麦角固醇复合的异黄酮类化合物（例如异黄酮菌素B）、抑制麦角固醇生物合成途径中的步骤的多种唑类和烯丙胺、抑制核酸合成的氟胞嘧啶和（1，3）β-葡聚糖合成酶抑制剂Cancidas。不幸的是，阿替霉素B具有许多急性和慢性副作用。 氟胞嘧啶具有窄的活性谱，并且由于耐药真菌的发展而受到治疗失败的困扰。 唑类药物仅具有抑菌作用，对常用唑类药物的耐药性正在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的作用机制的新型药物。 申请人的长期目标是发现对乙醛酸循环的酶有活性的新型抗真菌剂。 乙醛酸循环，这是在人类中不存在的，是必不可少的真菌致病性，并代表了一个未开发的抗真菌药物的发展途径。 研究人员将在两个目标中实现这一目标：（1）分离和鉴定5至10种乙醛酸循环酶的抑制剂，并确定其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具活性的化合物的体内功效。 最终，这项工作将导致分离出用于治疗人类真菌疾病的新型化合物。 申请人预测，由于人类没有乙醛酸循环，因此抑制剂将是安全有效的治疗剂。