Chemical Biology of Ant-Associated Defensive Bacteria

 描述（由申请人提供）：对新抗生素的需求继续增长。来自微生物来源的天然产物为新型抗生素提供了主要渠道，但传统的发现努力在过去几十年中产生了递减的回报，需要新的方法。该提案使用了将化学生态学与天然产品发现相结合的强大方法，利用了与真菌养殖蚂蚁相关的细菌的高产化学。这些高度专业化的蚂蚁相关细菌被认为是使用抗生素来保护自己的利基，对抗密切相关的竞争对手。这种拮抗作用的化学基础尚未探索，这是本项目的基础。本项目的第一个目的是筛选蚂蚁相关细菌，以确定抗菌活性和其他化学介导的相互作用。第二，负责这种活动的分子将被识别和表征。基因组测序将把这些活性分子与它们的生物合成基因簇联系起来，还能揭示哪些额外的簇存在但“沉默” - 即没有观察到相应的代谢物。这些“神秘的”生物合成簇是细菌基因组的一个近乎普遍的特征，也是抗生素发现的一个主要机会。第三个目标是使用生态启发的共培养方法来提供缺失的化学线索，这些化学线索引起这些“神秘”代谢物中的一些的产生。这些抗生素生产的化学诱导剂将被鉴定，测试其通用性，并应用于诱导额外的隐蔽代谢物。

 DESCRIPTION (provided by applicant): The need for new antibiotics continues to grow more dire. Natural products from microbial sources have supplied the major pipeline for novel antibiotics, but traditional discovery efforts have yielded diminishing returns over the last severl decades, necessitating new approaches. This proposal uses the powerful approach of aligning chemical ecology with natural product discovery, exploiting the highly productive chemistry of bacteria associated with fungus-farming ants. These highly specialized ant-associated bacteria are thought to defend their niche using antibiotics against closely related competitors. The chemical basis of this antagonism has not been explored and is the foundation of this project. The first aim of this project is to screen ant-associated bacteria to identify antibacterial activiy and other chemically mediated interactions. Second, the molecules responsible for this activity will be identified and characterized. Genome sequencing will connect these active molecules to their biosynthetic gene clusters and also reveal which additional clusters are present but "silent" - that is, no corresponding metabolites are observed. These "cryptic" biosynthetic clusters are a near-universal feature of bacterial genomes and are a major opportunity for antibiotic discovery. The third aim uses ecologically inspired co-culturing approaches to supply missing chemical cues that elicit production of some of these "cryptic" metabolites. These chemical inducers of antibiotic production will be identified, tested for general utility, and applied to elicit additioal cryptic metabolites.