COPROPHILOUS FUNGI--NEW SOURCES OF BIOACTIVE METABOLITES

这项提议要求支持继续和扩大调查 关于粪菌的天然产物化学。 这些很少- 所研究的真菌在生态学、形态学和分类学上 它们通常表现出对抗其他生物的对抗作用， 真菌 基于这些考虑和初步的积极成果， 粪生真菌作为新的抗真菌剂的来源显示出相当大的希望 天然产品。 这种性质的化合物可用于制备 开发人类真菌疾病的新疗法。 在该项目的前2.5年进行的研究提供了 几种新型抗真菌剂，其中一些具有不寻常的 化学结构。 许多其他的微生物， 对医学相关真菌的影响已经可以用于化学品 调查 虽然对这些生物体的研究正在进行中，但进一步 粪生物种将被分离、鉴定和预筛选， 抗真菌活性在实验室的专家在粪 真菌学（D. Malloch）。 要针对的真菌类型是那些 被认为最有可能表现出对抗活性 竞争对手，并将根据他们的知识选择 生态学和分类学。 发现具有抗真菌作用的分离株将 在液体培养中生长，并将在内部和 一家合作制药公司（礼来公司）， 化学研究。 抗真菌成分将通过现场分离 生物测定指导的分馏，并确定它们的结构 使用最先进的光谱技术。 抗真菌功效 将在礼来进一步评价新的代谢产物。 纯化合物将 还应测试其他重要活动，并优先考虑 与癌症相关的分析。 该项目有几个独特的方面。 具体目标是 粪生真菌作为抗真菌剂的来源是前所未有的。 没有一 本工作中包括的分离物（以及属的少数成员） 它们代表）曾经被化学研究过。 所提出的方法 依赖于生态学，分类学和/或新颖性的知识， 在化学研究之前， 去复制，增加发现新化学的几率， 防止重复调查大量研究的物种。 这 系统的、基于生态学的微生物选择方法代表了 与传统的随机微生物筛选程序不同， 试图在过程开始时引入合理性。 的 迄今取得的进展表明，研究小组有能力 进行拟议的研究，并强调需要继续 对这一相对未开发的潜在资源的调查 有价值的天然产品。

This proposal requests support to continue and expand an investigation of the natural products chemistry of coprophilous fungi. These rarely- studied fungi are ecologically, morphologically, and taxonomically distinctive, and they commonly display antagonistic effects against other fungi. Based on these considerations, and on initial positive results, coprophilous fungi show considerable promise as sources of new antifungal natural products. Compounds of this nature could be useful in the development of new treatments for fungal diseases in humans. Studies carried out in the first 2.5 years of this project have afforded several types of new antifungal agents, some of which possess unusual chemical structures. Many additional organisms that display inhibitory effects on medically relevant fungi are already available for chemical investigation. While studies of these organisms are in progress, further coprophilous species will be isolated, identified, and prescreened for antifungal activity in the laboratory of an expert in coprophilous mycology (Prof. D. Malloch). The types of fungi to be targeted are those considered most likely to exhibit antagonistic activity towards competitors, and will be selected on the basis of knowledge about their ecology and taxonomy. Isolates found to display antifungal effects will be grown in liquid culture, and extracts will be tested in-house and at a cooperating pharmaceutical company (Lilly) to prioritize cultures for chemical studies. Antifungal components will be isolated through on-site bioassay-guided fractionation, and their structures will be determined using state-of-the-art spectroscopic techniques. Antifungal potency of new metabolites will be further evaluated at Lilly. Pure compounds will also be tested for other important activities, with next priority given to cancer-relevant assays. The project has several unique aspects. The specific targeting of coprophilous fungi as sources of antifungals is unprecedented. None of the isolates to be included in this work (and few members of the genera they represent) have ever been studied chemically. The proposed approach relies upon knowledge of the ecology, taxonomy, and/or novelty of the organism prior to chemical investigation, thereby simplifying dereplication, increasing the odds of discovering new chemistry, and preventing repetitive investigation of heavily studied species. This systematic, ecology-based approach to microorganism selection represents a departure from traditional random microbial screening programs by attempting to introduce rationale at the beginning of the process. The progress made to date demonstrates the ability of the research team to perform the proposes studies, and underscores the need for continued investigation of this relatively unexplored source of potentially valuable natural products.