Inhibition of phage infection by secondary metabolites produced by actinobacterial species

放线菌属链霉菌的成员是具有广泛生物活性的天然产物的多产者。这种生物活性分子库已被用于医学和农业目的，例如，已知的微生物来源的抗生素中的20%是由链霉菌产生的。然而，在防御病毒感染的潜在作用最近才被认识到。噬菌体感染实际上如何改变宿主的抗生素谱，以及这种反应如何在多细胞水平上增加对病毒捕食的保护尚未得到解决。在初步实验中，我们已经分离和表征了超过15种感染不同链霉菌株的新型真菌。有趣的是，我们观察到强烈的生产次生代谢产物在感染区形成的斑块天蓝色链霉菌。此外，初步数据显示，不同的氨基糖苷类抗生素有效地保护链霉菌物种免受噬菌体捕食。 拟议的项目将侧重于两个主要目标。目的探讨噬菌体感染对链霉菌抗生素谱的影响及其在化学防御策略中的潜在作用。目的II将具体探讨氨基糖苷类抗生素的抗病毒"作用方式"。总的来说，不同目标的工作方案之间以及与最高优先级方案内的其他项目之间有很大的协同潜力。实验将包括密集的筛选以及分子/机制的方法来解决噬菌体感染的哪个阶段受到特定分子的影响的问题。总体而言，拟议项目中计划的实验将为链霉菌对噬菌体感染的化学防御提供重要的见解，并有可能在多细胞水平上发现抗病毒防御的新概念。

Members of the actinobacterial genus Streptomyces are prolific producers of natural products with a wide range of biological activities. This repertoire of bioactive molecules has been harnessed for medical and agricultural purposes, as for example ⅔ of known antibiotics of microbial origin are produced by Streptomyces. However, a potential role in defense against viral infection has only been recognized recently. How phage infection actually alters the antibiotic profile of the host and how this reaction may add to the protection against viral predation at the multicellular level has not been addressed yet. In preliminary experiments, we have isolated and characterized more than 15 novel phages infecting different Streptomyces strains. Interestingly, we observed intensive production of secondary metabolites at the infection zone in plaques formed by Streptomyces coelicolor phages. Furthermore, preliminary data revealed that different aminoglycoside antibiotics efficiently protect Streptomyces species from phage predation. The proposed project will focus on two main objectives. Objective I will address the impact of phage infection on the antibiotic profiles of Streptomyces strains and their potential role in chemical defense strategies. Objective II will specifically investigate the antiviral ‘mode of action’ of aminoglycoside antibiotics. Overall, there is a high potential for synergy between WPs of the different objectives as well as with further projects within the SPP. Experiments will cover intensive screenings as well as molecular/mechanistic approaches addressing the question which stage in phage infection is affected by the particular molecules.Overall, experiments planned in the proposed project will provide important insights into the chemical defense of Streptomyces to phage infection and have the potential to discover new concepts in antiviral defense at the multicellular level.