Key Laboratory of Tropical Marine Bioresources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
ACS Synth Biol. 2023 May 19;12(5):1520-1532. doi: 10.1021/acssynbio.3c00055. Epub 2023 Apr 21.
Ribosome-targeting oligosaccharides, everninomicins (EVNs), are promising drug leads with a unique mode of action distinct from that of currently used antibiotics in human therapy. However, the low yields in natural microbial producers hamper an efficient preparation of EVNs for detailed structure-activity relationship analysis. Herein, we enhance the production of EVNs by duplicating the biosynthetic gene cluster (BGC) in sp. SCSIO 07395 and thus obtain multiple EVNs that are sufficient for bioactivity evaluation. EVNs (-) are shown to significantly inhibit the growth of multidrug-resistant Gram-positive staphylococcal, enterococcal, and streptococcal strains and Gram-negative pathogens and , with micromolar to nanomolar potency, which are comparable or superior to vancomycin, linezolid, and daptomycin. Furthermore, the BGC duplication strategy is proven effective in stepwisely improving titers of the bioactive EVN M ) from the trace amount to 98.6 mg L. Our findings demonstrate the utility of a bioengineering approach for enhanced production and chemical diversification of the medicinally promising EVNs.
核糖体靶向寡糖（everninomicins，EVNs）是具有独特作用模式的有前途的药物先导物，与目前在人类治疗中使用的抗生素不同。然而，天然微生物生产者的产量低，阻碍了 EVNs 的有效制备，无法进行详细的结构-活性关系分析。在此，我们通过在 sp. SCSIO 07395 中复制生物合成基因簇（BGC）来提高 EVNs 的产量，从而获得了足够进行生物活性评估的多种 EVNs。结果表明，EVNs（-）可显著抑制多种耐药性革兰氏阳性葡萄球菌、肠球菌和链球菌以及革兰氏阴性病原体 和 的生长，其对这些病原体的抑制活性具有微摩尔至纳摩尔的效力，与万古霉素、利奈唑胺和达托霉素相当或更优。此外，BGC 复制策略被证明可有效逐步提高生物活性 EVN M 的产量，从痕量提高到 98.6 mg/L。我们的研究结果表明，生物工程方法可用于增强具有医学应用前景的 EVNs 的生产和化学多样化。
