The Microbial Battlefield: Streptomyces Anti-Phage Chemical Warfare

这笔赠款将研究链霉菌产生抗噬菌体次级代谢物的情况。噬菌体是感染和杀死细菌的病毒。它们是地球上最丰富的生物实体，数量是细菌的十分之一。据估计，阿沃加德罗感染噬菌体的数量在地球上每秒都会发生。这种无处不在的选择压力，加上环境中无处不在的噬菌体，导致了一系列细菌抗噬菌体防御机制的进化。例如，细菌可以使用限制性内切酶或CRISPR-Cas系统来抑制噬菌体在细胞表面的附着，阻止基因组复制，或者降解噬菌体基因组。鉴于细菌-噬菌体军备竞赛的激烈程度，其他防御机制很可能仍有待描述。这些机制的表征将为了解噬菌体与宿主的相互作用如何塑造微生物世界提供重要的见解。*先前对抑制大肠杆菌噬菌体复制的化合物的研究发现，不同种类的链霉菌产生的许多次生代谢物可以有效地阻止噬菌体的繁殖。我们在链霉菌菌株中鉴定这些次级代谢物的频率很高，这让我们假设次级代谢物提供了一种以前未知的抗噬菌体防御系统。在这项提案中，我们将确定链霉菌是否使用次生代谢物作为内源性抗噬菌体防御机制，并将确定这些分子合成的遗传途径。我们开发了一个进行这些研究的独特平台，将高通量筛选与详细的生化和遗传学研究相结合，使我们能够识别分子并将它们与抗噬菌体活性直接联系起来。这项工作将把生物学功能归因于以前未知的次生代谢物，并为细菌和噬菌体之间的进化军备竞赛提供新的见解，这在营养循环、全球气候、生物多样性和物种分布中发挥着重要作用。

This grant will investigate the production of anti-phage secondary metabolites by Streptomyces bacteria. Phages are viruses that infect and kill bacteria. They are the most abundant biological entity on earth, outnumbering bacteria by a factor of ten. It is estimated that Avogadro's number of phage infections occurs each second on earth. This pervasive selection pressure combined with the ubiquity of phages in the environment has led to the evolution of a wide array of bacterial anti-phage defense mechanisms. For example, bacteria can inhibit phage attachment at the cell surface, block genome replication, or degrade the phage genome using restriction enzymes or the CRISPR-Cas system. Given the intensity of the bacteria-phage arms race, it is highly probable that other defense mechanisms remain to be delineated. Characterization of these mechanisms will provide important insight into how phage-host interactions shape the microbial world. ******Previous studies searching for compounds that inhibit E. coli phage replication identified a number of secondary metabolites produced by different species of Streptomyces that actively block phage propagation. The high frequency with which we identified these secondary metabolites among Streptomyces strains led us to hypothesize that secondary metabolites provide a previously uncharacterized anti-phage defense system. In this proposal, we will determine if Streptomyces use secondary metabolites as an endogenous anti-phage defense mechanism and will identify genetic pathways through which these molecules are synthesized. We have developed a unique platform for pursuing these studies that combines high-throughput screening with detailed biochemical and genetic studies that will allow us to identify molecules and directly link them with anti-phage activities. This work will ascribe biological functions to previously uncharacterized secondary metabolites and provide new insight into the evolutionary arms race between bacteria and phages, which plays important roles in nutrient cycling, global climate, biodiversity, and species distribution.