A Dibenzo- p -dioxin-Shaped New Chemotype of Glycopeptide Antibiotic Active against Drug-Resistant Pathogens

作者：Xingkun Li, Mengru Wang, Lixin Yin, Jiawei Cao, R Wang, Xinzhu Wang, Qian Chen, Dexi Bi, Zhilong Zhao, Zixin Deng, Anwei Hou, Xu M · 发表于：ACS Infectious Diseases · 年份：2026 · DOI：10.1021/acsinfecdis.6c00042 · 被引用次数：2 · 研究领域：Carbohydrate Chemistry and Synthesis、Antimicrobial Peptides and Activities、Microbial Natural Products and Biosynthesis

Glycopeptide antibiotics (GPAs) are the drugs of “last resort” for treating multidrug-resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus and enterococci . Unfortunately, GPAs are vulnerable to resistance and the dissemination of various types of vancomycin-resistant determinants warrants the discovery of GPAs with novel chemical structures and modes of action (MOA). The overlooked GPAs from the type V subgroup adopt a unique MOA by interrupting cell wall remodeling and are promising lead candidates in antibiotic development. Herein, we describe the discovery of fumamycin from Streptomyces fumanus CGMCC 4.1732 through phylogenetic-guided genome mining and heterologous expression. Fumamycin is the first decapeptide scaffold GPA free of the conserved 4-hydroxyphenylglycine (Hpg) and tryptophan residues, and its peptide scaffold is cross-linked through a unique biaryl ether bond between two 3,5-dihydroxyphenylglycine (Dpg) residues at positions 1 and 3 in the decapeptide scaffold, and in particular, an unprecedented dibenzo- p -dioxin ring between tyrosine at position 6 (Tyr6) and Dpg at position 9 (Dpg9). Gene disruption determines the two P450s, FumD and FumE, are responsible for constructing the dibenzo- p -dioxin ring and the Dpg1- O -Dpg3 cross-link, respectively. Fumamycin represents a new-to-nature GPA chemotype beyond the existing type I–V GPA classification system, it inhibits bacterial growth through a similar manner to that of type V...