COPROPHILOUS FUNGI--NEW SOURCES OF BIOACTIVE METABOLITES

该提案请求支持以继续并扩大调查范围 嗜辅性真菌的天然产物化学。这些很少- 所研究的真菌在生态、形态和分类上都是 与众不同，而且它们通常表现出对抗其他 真菌。基于这些考虑，以及初步的积极结果， 共生真菌作为新的抗真菌来源显示出巨大的潜力 天然产品。这种性质的化合物可能在 人类真菌疾病新疗法的开发。 在该项目的前2.5年中进行的研究提供了 几种新的抗真菌药物，其中一些具有不同寻常的 化学结构。许多其他显示出抑制作用的生物体 对医学上相关的真菌的影响已经可以用于化学物质 调查。虽然对这些生物的研究正在进行中，但进一步 将分离、鉴定和预筛选亲水物种，以确定 共生真菌专家实验室中的抗真菌活性 真菌学(D.Malloch教授)。被列为目标的真菌种类包括 被认为最有可能表现出对抗活动的 参赛者，并将根据他们对自己的了解进行选择 生态学和分类学。被发现具有抗真菌作用的菌株将 在液体培养中生长，提取物将在室内和在 一家合作的制药公司(礼来公司)优先培养 化学研究。将通过现场分离抗真菌成分 生物测定引导的分离，并将确定其结构 使用最先进的光谱技术。丹参的抗真菌活性 礼来公司将进一步评估新的代谢物。纯化合物会 也要对其他重要活动进行测试，并优先考虑下一个 与癌症相关的化验。 该项目有几个独特的方面。特定的目标是 共生真菌作为抗真菌药物的来源是史无前例的。没有一个 将包括在这项工作中的分离物(以及少数属成员 它们代表)曾经被化学研究过。建议的方法 依赖于关于生态、分类和/或新颖性的知识 生物体，从而简化了化学研究 去突变，增加了发现新化学的几率，以及 防止对大量研究的物种进行重复调查。这 系统的、基于生态的微生物选择方法代表了 与传统的随机微生物筛选计划不同的是 试图在进程开始时介绍基本原理。这个 迄今为止取得的进展表明，研究小组有能力 执行建议研究，并强调需要继续 对这一相对未被探索的潜在来源的调查 珍贵的天然产品。

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.