SCREENING OF THERMOPHILES FOR ANTIFUNGAL ACTIVITY

在免疫功能低下的患者和接受积极的癌症化疗的患者中，越来越多地观察到深层真菌病。 用于治疗这些感染的可用药物的使用受到毒性和耐药真菌物种的出现的限制。 真菌感染对免疫功能低下患者临床管理的影响强调了对新抗真菌药物的明确需求。从历史上看，微生物和植物一直是治疗人类疾病的丰富药物来源。 这些微生物中的许多已经被筛选了无数次，降低了发现其他先导化合物的可能性。 避免这种障碍的一种方法是从不寻常和被忽视的生态系统中筛选微生物。 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。 本项目的总体目标是鉴定从嗜热微生物中分离的新的抗真菌化合物。 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有效活性的嗜热菌，并确定了一种归因于真菌特异性的作用机制。 在这个第二阶段的提案中，我们计划通过筛选额外的极端微生物来扩展第一阶段的工作，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5种化合物。建议的商业应用在第二阶段SBIR建议中概述的研究和开发将导致鉴定出一些主要的抗真菌化合物。 我们估计，一个新的和安全的抗真菌药物的市场潜力大于200，000，000美元/年。

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.