Sesbanimide R, a Novel Cytotoxic Polyketide Produced by Magnetotactic Bacteria

Abstract

Genomic information from various magnetotactic bacteria suggested that besides their common ability to form magnetosomes, they potentially also represent a source of bioactive natural products. By using targeted deletion and transcriptional activation, we connected a large biosynthetic gene cluster (BGC) of the trans-acyltransferase polyketide synthase (trans-AT PKS) type to the biosynthesis of a novel polyketide in the alphaproteobacterium Magnetospirillum gryphiswaldense. Structure elucidation by mass spectrometry and nuclear magnetic resonance spectroscopy (NMR) revealed that this secondary metabolite resembles sesbanimides, which were very recently reported from other taxa. However, sesbanimide R exhibits an additional arginine moiety the presence of which reconciles inconsistencies in the previously proposed sesbanimide biosynthesis pathway observed when comparing the chemical structure and the potential biochemistry encoded in the BGC. In contrast to the case with sesbanimides D, E, and F, we were able to assign the stereocenter of the arginine moiety experimentally and two of the remaining three stereocenters by predictive biosynthetic tools. Sesbanimide R displayed strong cytotoxic activity against several carcinoma cell lines. IMPORTANCE The findings of this study contribute a new secondary metabolite member to the glutarimide-containing polyketides. The determined structure of sesbanimide R correlates with its cytotoxic bioactivity, characteristic for members of this family. Sesbanimide R represents the first natural product isolated from magnetotactic bacteria and identifies this highly diverse group as a so-far-untapped source for the future discovery of novel secondary metabolites.

The Genomic-Driven Discovery of Glutarimide-Containing Derivatives from Burkholderia gladioli

“…Glutarimide antibiotics characterized by a glutarimide ring were derived mainly from Streptomyces in the past but were recently found in various strains, including Burkholderia, Pseudomonas, and other marine-derived strains [9][10][11][12][13]. These compounds exhibit widespread pharmacological effects, such as antitumor, anti-inflammatory, and antifungal.…”

“…Compounds 1 and 2 were determined to be gladiofungin A (or gladiostatin) and its degradation product, named gladiofungin C, via a comparison of its 1 H and 13 was connected to C-18 (δ H/C 2.33/33.9), supported by the HMBC correlation between H-18 and C-19 (Figures 2c and 3). Gladiofungin E (4) and gladiofungin F (5) were isolated as colorless oils.…”

“…Compounds 1 and 2 were determined to be gladiofungin A (or gladiostatin) and its degradation product, named gladiofungin C, via a comparison of its 1 H and 13 1 and 2) were similar…”

“…The other glutarimide family polyketides, secimide from P. syringae Molecules 2023, 28, 6937 2 of 12 pv. syringae and sesbanimides, biosynthesized by marine alphaproteobacterial strains, were also discovered [9,12,13] (Figure S1).…”

“…Molecules 2023, 28, x FOR PEER REVIEW 2 of 12 syringae pv. syringae and sesbanimides, biosynthesized by marine alphaproteobacterial strains, were also discovered [9,12,13] (Figure S1). These glutarimide-containing antibiotics were biosynthesized via trans-AT PKSs, which consist of multiple modules harboring various functional domains.…”