SCREENING OF THERMOPHILES FOR ANTIFUNGAL ACTIVITY

在免疫功能低下患者和接受积极癌症化疗的患者中，越来越多地观察到深层真菌病。治疗这些感染的现有药物的使用受到毒性和耐药真菌物种的出现的限制。真菌感染在免疫功能低下患者的临床管理中的影响强调了对新型抗真菌药物的明确需求。历史上，微生物和植物一直是治疗人类疾病药物的丰富来源。许多这些生物已经被筛选了很多次，减少了发现其他先导化合物的可能性。避免这一障碍的一种方法是从不寻常的和被忽视的生态系统中筛选出微生物。来自独特生态系统的嗜热生物代表了潜在生物活性化合物的未筛选来源。该项目的总体目标是从嗜热微生物中分离出新的抗真菌化合物。在第一阶段的工作中，我们已经确定了对几种人类真菌病原体具有强效活性的嗜热菌，并确定了一种特定于真菌的作用机制。在这个II期项目中，我们计划通过筛选更多的极端微生物来扩展I期工作，阐明10种抗真菌化合物的结构，并在临床前动物模型中测试其中的5种化合物。拟议的商业应用SBIR II期提案中概述的研究和开发将导致许多主要抗真菌化合物的鉴定。我们估计，一种新型安全的抗真菌药物的市场潜力每年超过2亿美元。

Deep-seated mycoses are being increasingly observed in immunocompromised patients and in patients receiving aggressive cancer chemotherapy. The use of available drugs for the treatment of these infections are limited by toxicity and the emergence of resistant fungal species. The impact of fungal infections in the clinical management of immunocompromised patients underscore the clear need for new antifungals. Historically microorganisms and plants have been rich sources of drugs for the treatment of human disease. Many of these organisms have been screened numerous times, decreasing the probability of finding additional lead compounds. One way to avoid this stumbling block is to screen microorganisms from unusual and ignored ecosystems. Thermophilic organisms from unique ecosystems represent an unscreened source of potential bioactive compounds. The overall goal of this project is to identify new antifungal compounds isolated form thermophilic microorganisms. In the Phase I work, we have identified thermophiles that have potent activity against several human fungal pathogens and have identified an ascribed fungal-specific mechanism of action. In this Phase II proposal, we plan to extend the Phase I work by screening additional extremophiles, elucidating the structures of ten antifungal compounds and testing five of these compounds in pre-clinical animal models. PROPOSED COMMERCIAL APPLICATION The research and development outlined in the Phase II SBIR proposal will lead to the identification of a number of lead antifungal compounds. We estimate that the market potential for a novel and safe antifungal drug to be greater than 200,000,000 dollars per year.