Yushchuk Oleksandr, Berini Francesca, Zhong Lei, Rückert-Reed Christian, Bernasconi Elena, Bartolone Letizia, Busche Tobias, Kalinowski Jörn, Süssmuth Roderich D, Marinelli Flavia
Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, Hrushevskoho St. 4, 79005, Lviv, Ukraine.
Department of Biotechnology and Life Sciences, University of Insubria, via J. H. Dunant 3, 21100, Varese, Italy.
Commun Chem. 2025 May 3;8(1):134. doi: 10.1038/s42004-025-01534-x.
Discovery of novel antibiotics is crucial to counteract bacterial resistance spread. Aiming to expand the available arsenal of last-resort glycopeptide antibiotics (GPAs), we mined the actinobacterial genomes of Pseudonocardiales. We thus identified a biosynthetic gene cluster (BGC) encoding for a GPA with a novel peptide scaffold, not fitting into the existing classification of GPA types. By cultivating the producer strain, Actinokineospora auranticolor DSM 44650, an antibiotic complex-named kineomicins (Kmc)-was identified and characterized by microbiological assays, LC-MS, and MS/MS analyses. A comprehensive model for Kmc biosynthesis was then proposed by a thorough investigation of kineomicin BGC (knm). The structure of the main complex congener (KmcB), resolved by NMR spectroscopy, proved to be unique. Finally, the remarkably high antibiotic production rate, up to >1 g L Kmc in benchtop bioreactor, indicated A. auranticolor as a natural GPA overproducer, holding promise as a potential host for heterologous expression of GPA BGCs.
发现新型抗生素对于对抗细菌耐药性传播至关重要。为了扩充可用的最后手段糖肽类抗生素（GPA）储备，我们挖掘了诺卡氏菌目的放线菌基因组。因此，我们鉴定出一个生物合成基因簇（BGC），其编码一种具有新型肽支架的GPA，不符合现有的GPA类型分类。通过培养产生菌菌株——金色动孢菌DSM 44650，一种名为动霉素（Kmc）的抗生素复合物被鉴定出来，并通过微生物学测定、液相色谱-质谱联用（LC-MS）和串联质谱（MS/MS）分析进行了表征。通过对动霉素生物合成基因簇（knm）的深入研究，随后提出了一个Kmc生物合成的综合模型。通过核磁共振光谱解析的主要复合物同源物（KmcB）的结构被证明是独特的。最后，在台式生物反应器中高达>1 g/L Kmc的显著高抗生素生产率表明，金色动孢菌是一种天然的GPA高产菌，有望成为GPA BGC异源表达的潜在宿主。
