Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmaceutical Biotechnology, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany).
Chembiochem. 2013 Sep 2;14(13):1573-80. doi: 10.1002/cbic.201300140. Epub 2013 Aug 19.
Myxobacteria have proven to be highly valuable sources of natural products, as they produce a variety of secondary metabolites with unique structures and often new modes of action. In this study, high-content screening is demonstrated to be a convenient tool for bioactivity-guided isolation of natural products from crude bacterial extracts. By the application of focused, image-based screens we were able to identify over 30 novel chondramide derivatives from Chondromyces sp. MSr9030, some of which were present in only minute amounts. These cyclic depsipeptides were shown to target actin filaments with a similar binding mode to that of the mushroom toxin phalloidin. Fermentations of the myxobacterial strain were carried out under improved cultivation conditions, and supplementation of the culture broth with potassium bromide afforded the production of brominated analogues that are superior (in terms of biological activity) to all chondramides described to date. Initial biological profiling of 11 new derivatives in comparison to the reference compounds (chondramides A-C) showed that bromo-chondramide C3 and propionyl-bromo-chondramide C3 are the most active in cell-based studies, with GI₅₀ values on human cancer cell lines in the low nanomolar range. Given that these brominated C3 analogues were also less potent on noncancerous human cells (by a factor of 2 to 4 in comparison to cancer cell lines), our results can aid further structure-activity relationship-guided development of chondramides, either as molecular probes or pharmaceutical agents.
黏细菌已被证明是天然产物的极具价值的来源，因为它们产生了具有独特结构和新颖作用模式的各种次级代谢产物。在这项研究中，高内涵筛选被证明是一种从粗提细菌提取物中进行生物活性导向的天然产物分离的便捷工具。通过应用有针对性的、基于图像的筛选，我们能够从 Chondromyces sp. MSr9030 中鉴定出 30 多种新型海绵抑素衍生物，其中一些仅以微量存在。这些环状脱肽抗生素与蘑菇毒素鬼笔环肽具有相似的结合模式，靶向肌动蛋白丝。对黏细菌菌株进行发酵，并在改良的培养条件下进行，向培养液中补充溴化钾可产生溴代类似物，其在生物活性方面优于迄今为止描述的所有海绵抑素。与参考化合物（海绵抑素 A-C）相比，对 11 种新衍生物进行的初步生物学特征分析表明，溴代海绵抑素 C3 和丙酰基-溴代海绵抑素 C3 在基于细胞的研究中最为活跃，对人类癌细胞系的 GI₅₀ 值在纳摩尔范围内。鉴于这些溴代 C3 类似物对非癌细胞（与癌细胞系相比，活性降低 2 至 4 倍）的活性也较低，我们的结果可以帮助进一步进行基于结构活性关系的海绵抑素的开发，无论是作为分子探针还是药物制剂。
