Department of Microbiology, University of Bayreuth, Bayreuth, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany.
mBio. 2021 May 18;12(3):e00591-21. doi: 10.1128/mBio.00591-21.
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 -acyltransferase polyketide synthase (-AT PKS) type to the biosynthesis of a novel polyketide in the alphaproteobacterium 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. 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.
从各种磁细菌的基因组信息表明,除了它们共同形成磁小体的能力外,它们还可能是生物活性天然产物的来源。通过靶向缺失和转录激活,我们将聚酮合酶(-AT PKS)型的酰基转移酶聚酮合酶(-AT PKS)大型生物合成基因簇(BGC)与α变形菌中的一种新型聚酮的生物合成连接起来。 通过质谱和核磁共振波谱(NMR)的结构阐明表明,这种次级代谢产物类似于最近从其他分类群中报道的 sesbanimides。然而,sesbanimide R 表现出额外的精氨酸部分,其存在解决了在比较 BGC 中编码的化学结构和潜在生物化学时观察到的先前提出的 sesbanimide 生物合成途径中的不一致性。 与 sesbanimides D、E 和 F 不同,我们能够通过预测生物合成工具实验分配精氨酸部分的立体中心和剩余三个立体中心中的两个。Sesbanimide R 对几种癌细胞系表现出强烈的细胞毒性活性。这项研究的发现为含有戊二酰亚胺的聚酮类化合物增添了一种新的次级代谢产物成员。Sesbanimide R 的确定结构与其细胞毒性生物活性相关,这是该家族成员的特征。Sesbanimide R 代表从磁细菌中分离出的第一个天然产物,并将这个高度多样化的群体确定为未来发现新型次级代谢产物的未开发来源。