Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived Streptomyces sp. IB201691-2A.

Irina Voitsekhovskaia,Yuriy Rebets,Suvd Nadmid,Christian Rückert,Alexandra K Kiemer,Josef Zapp,Maxim Timofeyev,Constanze Paulus,Andriy Luzhetskyy,Denis Axenov-Gribanov,Jörn Kalinowski,Charlotte Dahlem

doi:10.3390/microorganisms8050680

Abstract

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.

Highlights

Angucyclines are by far the largest group of aromatic polyketides solely produced by actino1b
Streptomyces albus J1074 was used as a host for the heterologous expression of the baikalomycin biosynthetic gene cluster [32]
Actinobacteria strains were cultured on soya flour mannitol agar (MS) medium and in liquid tryptic soy broth medium

Summary

Introduction

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Objectives

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Results