Phylogeny-Informed Discovery of New Glycopeptide Antibiotics Produced by a Minimal Biosynthetic Gene Cluster

Glycopeptide antibiotics (GPAs) are the frontline medicines to treat multidrug-resistant Gram-positive infections. Resistance to GPAs warrants the development of new antibiotics. Phylogeny reclassification of GPA biosynthetic gene clusters with a focus on the type V subgroup bearing a heptapeptide scaffold identified new GPAs, varsomycins, possessing unprecedented 3,5-dihydroxyphenylalanine at position 5 and an F-G biphenyl cross-link. Varsomycins are broadly active against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus and are promising lead compounds for resistance-oriented drug innovation.