Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
School of Chemistry and Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
J Nat Prod. 2022 Jun 24;85(6):1641-1657. doi: 10.1021/acs.jnatprod.2c00444. Epub 2022 May 31.
Chemical investigation of Australian pasture plant-derived sp. CMB-PB041, supported by miniaturized cultivation profiling and molecular network analysis, led to the isolation and characterization of 13 new macrocyclic spirotetronates, glenthmycins A-M (-), with structures assigned by detailed spectroscopic analysis, chemical degradation and derivatization, and mechanistic and biosynthetic considerations. Hydrolysis of glenthmycin B () yielded the aglycone , whose structure and absolute configuration were secured by X-ray analysis, along with the unexpected amino sugar residues glenthose lactams A () and B (), with Mosher analysis of facilitating assignment of absolute configurations of the amino sugar. While the glenthmycins proved to be acid stable, treatment of isomeric glenthmycins (i.e., , , and ) with base catalyzed rapid intramolecular -esterification to regio-isomeric mixtures (i.e., + + ). Exposure of to base achieved the same intramolecular -esterification and was instrumental in detecting and tentatively identifying two additional minor co-metabolites, glenthmycins N () and O (). A structure-activity relationship analysis carried out on - and the semisynthetic analogues and - revealed a promising Gram +ve antibacterial pharmacophore, effective against methicillin-resistant (MRSA) and vancomycin-resistant Enterococci (VRE), but with no detectable cytotoxicity to eukaryotic cells (i.e., fungal and human carcinoma). Of particular note, the semisynthetic analogue glenthmycin K 9-valerate () was unique among glenthmycins in potently inhibiting growth of the full panel of Gram +ve pathogens (IC 0.2-1.6 μM). We conclude with an observation that any future evaluation of the antibacterial potential of glenthmycins and related macrocyclic spirotetronates may do well to include important soil-derived Gram +ve pathogens, such as , , and , the causative agents of anthrax, botulism, and livestock pneumonia.
澳大利亚牧场植物衍生的 sp. CMB-PB041 的化学研究，通过微型培养分析和分子网络分析支持，导致了 13 种新的大环螺缩酮内酯的分离和表征，glenthmycins A-M (-)，通过详细的光谱分析、化学降解和衍生化、以及机械和生物合成考虑来确定结构。glenthmycin B ()的水解生成糖苷配基 ，其结构和绝对构型通过 X 射线分析确定，以及意想不到的氨基糖残基 glenthose lactams A ()和 B ()，通过 Mosher 分析有助于确定氨基糖的绝对构型。虽然 glenthmycins 被证明是酸稳定的，但用碱催化对异构的 glenthmycins（即 、 、和 ）进行处理导致区域异构混合物（即 + + ）的快速分子内 -酯化。将 暴露于碱中实现了相同的分子内 -酯化，并有助于检测和暂定鉴定另外两种次要共代谢物，glenthmycins N ()和 O ()。对 -和半合成类似物 和 -进行的构效关系分析显示了一种有前途的革兰氏阳性抗菌药效团，对耐甲氧西林金黄色葡萄球菌（MRSA）和万古霉素耐药肠球菌（VRE）有效，但对真核细胞（即真菌和人癌细胞）没有检测到细胞毒性。值得注意的是，半合成类似物 glenthmycin K 9-戊酸酯 ()在抑制革兰氏阳性病原体全谱的生长方面是 glenthmycins 中独一无二的（IC 0.2-1.6 μM）。我们的结论是，对 glenthmycins 和相关大环螺缩酮内酯的抗菌潜力的任何未来评估都可能很好地包括重要的土壤衍生的革兰氏阳性病原体，如炭疽、肉毒梭菌和家畜肺炎的病原体。
