Hidden for Decades: Overlooked Antibiotic Intermediate Is ~100× More Potent Against MRSA and VRE

A previously overlooked molecule offers a promising new tactic against superbugs

Antimicrobial resistance (AMR) — the rise of bacteria that withstand current antibiotics — is a growing global threat. The World Health Organization has warned that AMR could contribute to as many as 10 million deaths per year by 2050 if new solutions are not found. In a recent paper in the Journal of the American Chemical Society, researchers from Monash University and the University of Warwick report a striking discovery: an intermediate compound in a long-known antibiotic pathway shows dramatically greater potency than the finished product.

What the researchers found

The team studied the soil bacterium Streptomyces coelicolor — a member of a genus that has produced roughly two-thirds of naturally derived antibiotics. Although the antibiotic Methylenomycin A was synthesized decades ago (in the 1970s), scientists had not systematically tested the transient molecules formed along its biosynthetic pathway. By genetically deleting the genes that complete the pathway, the researchers were able to accumulate and isolate intermediate compounds for direct testing.

Of two newly characterized intermediates, one — named pre-methylenomycin C lactone — demonstrated exceptional activity in laboratory assays. In these tests it was roughly 100 times more potent than typical antibiotics against several Gram-positive pathogens, notably Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE). Under conditions that normally induce vancomycin resistance, VRE showed no signs of resistance to this intermediate in the experiments reported.

“By identifying and testing intermediates in the pathways to diverse natural compounds, we may find potent new antibiotics with more resilience to resistance that will aid us in the fight against AMR,” said Greg Challis of the University of Warwick.

Why this matters — and what comes next

This approach reframes how researchers look for antibiotic leads: instead of screening only final natural products, scientists can interrupt biosynthetic pathways to reveal hidden, bioactive intermediates. That may offer a faster, less costly route to promising compounds — important because antibiotic development is expensive and private investment is limited.

The team cautions the result is still early-stage. Pre-methylenomycin C lactone will move into pre-clinical trials, where chemists will study its chemical structure in detail, synthesize and test analogs to improve potency, safety, and manufacturability, and evaluate pharmacology and toxicity in relevant models. Success in lab assays does not guarantee safety or efficacy in humans, so further work is essential.

Nevertheless, this finding suggests a practical, hypothesis-driven search strategy for new antibiotics: mine known biosynthetic pathways for overlooked intermediates that may already possess strong antimicrobial activity. If this tactic yields additional leads, it could help tip the balance in the ongoing arms race between antibiotics and resistant bacteria.