Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams.

Yuchan Chen,Qingbo Zhang,Liping Zhang,Zhigang She,Hongbo Jin,Guangtao Zhang,Wenjun Zhang,Changsheng Zhang,Wei Liu,Weimin Zhang,Xiaodong Jiang

doi:10.3390/md17120663

Abstract

Polycyclic tetramate macrolactams (PTMs) biosynthetic gene cluster are widely distributed in different bacterial types, especially in Streptomyces species. The mining of the genomic data of marine-derived Streptomyces sp. SCSIO 40010 reveals the presence of a putative PTM-encoding biosynthetic gene cluster (ptm′ BGC) that features a genetic organization for potentially producing 5/5/6 type of carbocyclic ring-containing PTMs. A fermentation of Streptomyces sp. SCSIO 40010 led to the isolation and characterization of six new PTMs 1–6. Comprehensive spectroscopic analysis assigned their planar structures and relative configurations, and their absolute configurations were deduced by comparing the experimental electronic circular dichroism (ECD) spectra with the reported spectra of the known PTMs. Intriguingly, compounds 1–6 were determined to have a trans-orientation of H-10/H-11 at the first 5-membered ring, being distinct from the cis-orientation in their known PTM congeners. PTMs 1–5 displayed cytotoxicity against several cancer cell lines, with IC50 values that ranged from 2.47 to 17.68 µM.

Highlights

Polycyclic tetramate macrolactams (PTMs) are a unique class of natural products that consist of a tetramate-embedding macrocyclic lactam core and a varying carbocycle with 5/6, 5/5, 5/6/5, or 5/5/6 ring system [1]
The strain SCSIO 40010 was isolated from the mangrove sediment in Penang, Malaysia, and it was identified to be a Streptomyces species on the basis of its 16S rDNA sequence (GenBank accession number MN224032)
SCSIO 40010 reveals the presence of a putative PTM biosynthetic gene cluster (BGC) that displays high similarity to the PTM-encoding biosynthetic gene cluster (ptm BGC) in S. pactum SCSIO 02999 (Figure 2a) [20]

Summary

Introduction

Polycyclic tetramate macrolactams (PTMs) are a unique class of natural products that consist of a tetramate-embedding macrocyclic lactam core and a varying carbocycle with 5/6, 5/5, 5/6/5, or 5/5/6 ring system [1]. PTMs display a wide range of antifungal, antibiotic, antiprotozoal, and antitumor properties [2,3,4,5], and they have significant potential for applications in agricultures and medicines [1,6]. HSAF ( known as dihydromaltophilin) [7], a typical representative of 5/5/6 type of PTMs, exhibits a broad spectrum of antifungal activities and it has been used as an antifungal agent to control plant diseases [8]. The anticancer agent ikarugamycin [9], a typical 5/6/5 type of PTMs, shows activity as an inhibitor of clathrin-mediated endocytosis [10].

Methods

Results

Conclusion