Marine Actinomyceten als neue Quelle für die Entdeckung von Medikamenten in der Krebstherapie

这项研究项目的长期目标是寻找治疗癌症的新药物。这项延期提案的总体目标是继续并完成从以前从海洋沉积物中分离的活性筛选放线菌中分离和完成新的天然产物的结构鉴定。这些丰富但几乎未被开发的生物体已经进化成产生化学上独特的生物活性代谢物的集合。中心假设是进化上相关的海洋放线菌群(系统型)产生相关的分子套件(化学型)。上个月，对海洋放线菌菌株提取物的广泛研究证实了这一假设。在培养中获得和探索新的系统类型是发现天然产物的有效方法。对这些系统类型的基因组测序揭示了一个复杂的次生代谢体，甚至超出了观察到的化学类型1。我们随后的假设是，沉默基因簇的刺激激活将导致迄今尚未观察到的次生代谢物的产生。如果这两个假设都被证明是正确的，基于从这些系统类型中分离出新的天然产物，这项研究将极大地提高微生物天然产物发现的效率。

The long-term goal of this research project is to identify novel agents for the treatment of cancer. The overall objective of this extension proposal is to continue and finish the isolation and structure elucidation of new natural products from previous activity-screened actinomycetes, which were isolated from ocean sediments. These plentiful, yet virtually unexplored, organisms have evolved to produce collections of chemically unique, bioactive metabolites. The central hypothesis is that groups of evolutionarily-related marine actinomycetes (phylotypes) produce related suites of molecules (chemotypes). This hypothesis could be substantiated during the last month by extensively studies of strain extracts derived from marine actinomycetes. Obtaining and explore new phylotypes in culture is an effective method for natural product discovery. Genome sequencing on these phylotypes reveals a complex secondary metabolome even beyond the observed chemotypes1. Our subsequent hypothesis is that stimulated activation of silent gene clusters will lead to production of so far not observed secondary metabolites. If both hypotheses prove to be true based upon the isolation of new natural products from these phylotypes, this research could dramatically increase the efficiency of microbial natural products discovery.