Researchers identified a previously untested biosynthetic intermediate—pre‑methylenomycin C lactone—from Streptomyces coelicolor that shows markedly higher activity against Gram‑positive pathogens than the classical methylenomycin A. In JACS‑reported work, gene deletions in the biosynthetic pathway uncovered late intermediates with increased potency, including more than 100‑fold improved activity against Staphylococcus aureus and Enterococcus faecium. The discovery resurrects interest in revisiting known antibiotic pathways and screening intermediates that may have been overlooked in decades‑old model organisms. Authors emphasize the value of biosynthetic gene manipulation to reveal cryptic chemical diversity with therapeutic potential. The finding offers a preclinical lead against resistant Gram‑positive infections and reinvigorates natural‑product discovery strategies targeting AMR.