POTENTIATORS OF FLUCONAZOLE ACTIVITY IN CANDIDA

氟康唑在念珠菌中的活性增效剂

• 批准号: 2867941
• 负责人: Penelope N. Markham
• 金额: $ 9.98万
• 依托单位: PROTEZ PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2867941
• 关键词: Candida; antifungal agents; chemical registry /resource; chemical structure function; chemical synthesis; drug adverse effect; drug design /synthesis /production; drug interactions; drug resistance; drug screening /evaluation; fluconazole

There is an increasing incidence of life-threatening systemic fungal infections due to Candida species. Although fluconazole is currently the most widely used drug for preventing and treating these infections, its effectiveness is compromised, not only by the fact that it is fungistatic, but also by the recent emergence of fluconazole-resistant Candida strains. The therapeutic options for treating fluconazole-resistant Candida infections are limited to drugs with severe toxicity. In this project we plan to test the feasibility of developing an improved antifungal agent by potentiating the activity of fluconazole. A chemical library will be screened, first, for compounds which exhibit fungicidal activity in combination with fluconazole and, second, for compounds potentiating fluconazole activity in strains exhibiting intrinsic or acquired fluconazole resistance mechanisms. Preliminary screening of a portion of this library has already identified a promising candidate potentiator. The potentiating effects of the identified compounds will be quantitated and characterized and preliminary toxicity testing and structure activity analysis will be performed.The combination of fluconazole with a potentiator of its activity could form a powerful combination antifungal agent and extend the therapeutic options currently available for treating Candida infections. PROPOSED COMMERCIAL APPLICATIONS: The envisioned commercial product is a combination of fluconazole with a drug which potentiates its antifungal activity. Such a combination drug would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections.

由念珠菌引起的危及生命的全身真菌感染的发生率不断增加。尽管氟康唑是目前预防和治疗这些感染最广泛使用的药物，但其有效性受到损害，不仅因为它具有抑制真菌的作用，而且还因为最近出现的对氟康唑耐药的念珠菌菌株。治疗氟康唑耐药念珠菌感染的治疗选择仅限于具有严重毒性的药物。在这个项目中，我们计划测试通过增强氟康唑的活性来开发改进的抗真菌剂的可行性。首先，将筛选化学库，寻找与氟康唑组合表现出杀真菌活性的化合物，其次，筛选在表现出内在或获得性氟康唑抗性机制的菌株中增强氟康唑活性的化合物。对该文库的一部分的初步筛选已经确定了一个有前途的候选增效剂。将对已鉴定化合物的增强作用进行定量和表征，并进行初步毒性测试和结构活性分析。氟康唑与其活性增强剂的组合可以形成强大的组合抗真菌药物，并扩展目前可用于治疗的治疗选择念珠菌感染。拟议的商业应用：设想的商业产品是氟康唑与增强其抗真菌活性的药物的组合。这种组合药物将对全身念珠菌感染的治疗和预防治疗选择产生重大影响。