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

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 GPAs by binding to peptidoglycan and blocking the activity of autolysins, suggesting a conserved MOA distinct from type I-IV GPAs that inhibit cell wall biosynthesis by binding to d-Alanyl-d-Alanine motif in lipid II, and providing new lead compounds for developing antibiotics to mitigate antimicrobial resistance.