Global Activators of Fungal Natural Products

传染病是全球第二大死亡原因。越来越多的抗药性 微生物加剧了这一健康问题，世界卫生协会认为这一问题是 一个主要的公众关注。抗菌剂的发现始于青霉素生产的偶然发现 不久之后，更多的天然产品--大多数是细菌衍生的--被 在疾病治疗中得到确认和实施。尽管人们知道真菌会产生无穷无尽的 作为新型天然产物的来源，使用真菌来开采抗菌剂在很大程度上被废弃， 这些生物体中代谢物生产的看似不可接近的性质。在这里，我们证明， 真菌次级代谢产物生产的基因组知识的巨大进步，再一次， 打开了真菌药物开采的大门。利用已测序的模式子囊菌构巢曲霉，我们 提出三个目标： 1.为了激活全球次级代谢物调节器能够遗传操纵真菌进入总理 代谢产物的产生。 2.开发提高真菌次级代谢产物产量的通用工具。 3.将目标1和目标2中新鉴定的化合物用于主要真菌和真菌的生物测定， 细菌病原体 这项工作将提供针对主要感染性微生物群体的新化合物的开发， 最终应该导致适用的新抗菌剂，以增加美国和全球公众的健康。

Infectious disease is the second leading cause of death worldwide. The increasing number of drug resistant microbes exacerbates this health problem, a problem that is recognized by the World Health Association as a major public concern. Antimicrobial discovery began with the fortuitous discovery of penicillin production by the fungus Penicillium and, soon after, many more natural products - most often bacterially derived - were identified and implemented in disease treatment. Despite an understanding that fungi produce an endless source of novel natural products, the use of fungi to mine antimicrobials was largely scrapped due to the seemingly inaccessible nature of metabolite production in these organisms. Here we demonstrate that immense advances in genomic knowledge of fungal secondary metabolite production now, once again, opens the door to drug mining from fungi. Using the sequenced model ascomycete Aspergillus nidulans, we propose three aims: 1. To activate global secondary metabolite regulators able to genetically manipulate the fungus into prime metabolite production. 2. To develop generic tools for increased secondary metabolite production in fungi. 3. To transition the newly identified compounds in aims 1 and 2 to bioassays of major groups of fungal and bacterial pathogens. This work will provide development of new compounds against major groups of infectious microbes that should ultimately lead to applicable new antimicrobials to increase the health of the US and worldwide public.