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 Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis. 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 S. albus 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.
biology, glycosyltransferase, Streptomyces, natural products, pharmaceutical, angucycline, aquayamycin, Lake Baikal
NCBI PubMed ID: 32392775Publication DOI: 10.3390/microorganisms8050680Journal NLM ID: 101625893Publisher: Basel, Switzerland: MDPI AG
Correspondence: a.luzhetskyy@mx.uni-saarland.de
Institutions: Institute of Biology, Irkutsk State University, Irkutsk, Russia, Helmholtz Institute for Pharmaceutical Research Saarland, 66123 Saarbrücken, Germany, Pharmaceutical Biology, Saarland University, 66123 Saarbrucken, Germany, Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany, Baikal Research Centre, Irkutsk, Russia, Technology Platform Genomics, Center for Biotechnology (CeBiTec), Bielefeld University, 33615 Bielefeld, Germany
Methods: 13C NMR, 1H NMR, NMR-2D, PCR, MS/MS, chemical methods, HPLC, UV, LC-MS, function analysis of gene clusters, phylogenetic analysis, HR-ESI-MS, sequencing, biological activity assays
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