Voitsekhovskaia Irina, Paulus Constanze, Dahlem Charlotte, Rebets Yuriy, Nadmid Suvd, Zapp Josef, Axenov-Gribanov Denis, Rückert Christian, Timofeyev Maxim, Kalinowski Jörn, Kiemer Alexandra K, Luzhetskyy Andriy
Institute of Biology, Irkutsk State University, 664003 Irkutsk, Russia.
Helmholtz Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany.
Microorganisms. 2020 May 7;8(5):680. doi: 10.3390/microorganisms8050680.
Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new sp. strain IB201691-2A from the Lake Baikal endemic mollusk . In the course of an activity guided screening three new angucyclines, named baikalomycins A-C, were isolated and characterized, highlighting the potential of poorly investigated ecological niches. Besides that, the strain was found to accumulate large quantities of rabelomycin and 5-hydroxy-rabelomycin, known shunt products in angucyclines biosynthesis. Baikalomycins A-C demonstrated varying degrees of anticancer activity. Rabelomycin and 5-hydroxy-rabelomycin further demonstrated antiproliferative activities. The structure elucidation showed that baikalomycin A is a modified aquayamycin with β-d-amicetose and two additional hydroxyl groups at unusual positions (6a and 12a) of aglycone. Baikalomycins B and C have alternating second sugars attached, α-l-amicetose and α-l-aculose, respectively. The gene cluster for baikalomycins biosynthesis was identified by genome mining, cloned using a transformation-associated recombination technique and successfully expressed in J1074. It contains a typical set of genes responsible for an angucycline core assembly, all necessary genes for the deoxy sugars biosynthesis, and three genes coding for the glycosyltransferase enzymes. Heterologous expression and deletion experiments allowed to assign the function of glycosyltransferases involved in the decoration of baikalomycins aglycone.
在诸如贝加尔湖等不寻常且研究较少的生态系统中发现的细菌所产生的天然产物，是新的有价值药物先导物的一个有前景的来源。在此，我们报告从贝加尔湖特有的软体动物中分离出一种新的 sp. 菌株IB201691 - 2A。在活性导向筛选过程中，分离并鉴定了三种新的安古霉素，命名为贝加尔霉素A - C，突出了研究较少的生态位的潜力。除此之外，该菌株被发现积累了大量的拉贝洛霉素和5 - 羟基拉贝洛霉素，它们是安古霉素生物合成中已知的分流产物。贝加尔霉素A - C表现出不同程度的抗癌活性。拉贝洛霉素和5 - 羟基拉贝洛霉素进一步表现出抗增殖活性。结构解析表明，贝加尔霉素A是一种修饰的水霉素，在糖苷配基的不寻常位置（6a和12a）带有β - d - 阿米糖和另外两个羟基。贝加尔霉素B和C分别连接有交替的第二种糖，α - l - 阿米糖和α - l - 阿库洛糖。通过基因组挖掘鉴定了贝加尔霉素生物合成的基因簇，使用转化相关重组技术进行克隆并在J1074中成功表达。它包含一组负责安古霉素核心组装的典型基因、脱氧糖生物合成所需的所有基因以及三个编码糖基转移酶的基因。异源表达和缺失实验使我们能够确定参与贝加尔霉素糖苷配基修饰的糖基转移酶的功能。
