Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucı́a, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento 34, 18016, Armilla, Granada, Spain.
J Nat Prod. 2020 Sep 25;83(9):2597-2606. doi: 10.1021/acs.jnatprod.0c00294. Epub 2020 Sep 12.
A reinvestigation of the acetone extract of the strain CA-091830 of , producer of the imipenem potentiator krisynomycin, resulted in the isolation of two additional analogues, krisynomycins B () and C (), with different chlorination patterns. Genome sequencing of the strain followed by detailed bioinformatics analysis led to the identification of the corresponding biosynthetic gene cluster (BGC) of this cyclic nonribosomal peptide family. The planar structure of the new molecules was determined using HRMS, ESI-qTOF-MS/MS, and 1D and 2D NMR data. Their absolute configuration was proposed using a combination of Marfey's and bioinformatic BGC analyses. The krisynomycins displayed weak to negligible antibiotic activity against methicillin-resistant (MRSA), which was significantly enhanced when tested in combination with sublethal concentrations of imipenem. The halogenation pattern plays a key role in the antimicrobial activity and imipenem-potentiating effects of the compounds, with molecules having a higher number of chlorine atoms potentiating the effect of imipenem at lower doses.
对产亚胺培南增效剂克雷斯霉素的菌株 CA-091830 的丙酮提取物进行重新研究，分离得到两种新的类似物，克雷斯霉素 B()和 C()，其氯化模式不同。对该菌株进行基因组测序，然后进行详细的生物信息学分析，确定了该环状非核糖体肽家族的相应生物合成基因簇 (BGC)。利用高分辨质谱、ESI-qTOF-MS/MS 以及 1D 和 2D NMR 数据确定了新分子的平面结构。采用 Marfey 法和生物信息 BGC 分析相结合的方法提出了它们的绝对构型。克雷斯霉素对耐甲氧西林金黄色葡萄球菌 (MRSA) 的抗生素活性较弱或可忽略不计，但与亚胺培南的亚致死浓度联合使用时，其活性显著增强。卤化模式在化合物的抗菌活性和增强亚胺培南作用方面起着关键作用，具有更多氯原子的分子在较低剂量下增强亚胺培南的作用。
