Hidden Soil Antibiotic Shows Promise Against MRSA and Drug‑Resistant Enterococcus — Early Study

Researchers unexpectedly identify a potent new antibiotic intermediate

Scientists report the discovery of a previously hidden molecule, pre‑methylenomycin C lactone, that shows promising activity against drug‑resistant Gram‑positive bacteria. The finding, published Oct. 27 in the Journal of the American Chemical Society, emerged not from a drug screen but from efforts to map how a soil bacterium produces an existing antibiotic.

How the discovery happened

The research team, led by chemists Lona Alkhalaf and Greg Challis, studied the biosynthesis of methylenomycin A in the soil microbe Streptomyces coelicolor. By deleting individual genes in the bacterium's biosynthetic gene cluster, they interrupted the enzyme pathway at defined steps, allowing isolation of intermediate products. This approach yielded two previously unidentified compounds, pre‑methylenomycin C and its lactone form.

Activity against drug‑resistant bacteria

After rigorous structural analysis, the team tested the molecules against a panel of bacterial strains. The lactone, pre‑methylenomycin C lactone, showed particularly strong activity against Gram‑positive pathogens, notably methicillin‑resistant Staphylococcus aureus (MRSA) and a multidrug‑resistant strain of Enterococcus faecium. According to the authors, the lactone is roughly 100× more effective at killing some drug‑resistant bacteria than the original methylenomycin A in their assays.

Resistance testing and limitations

Early experiments also examined whether repeated exposure would select for resistance. In a 28‑day experiment with increasing concentrations of the lactone, the minimum inhibitory concentration (MIC) for E. faecium did not change, suggesting no detectable resistance emerged under those conditions. The authors emphasize, however, that broader testing across more strains and longer timeframes is needed to assess the true resistance potential.

Expert caution: "This is a really nice study," said Stephen Cochrane, a medicinal chemist at Queen's University Belfast not involved in the work, "but there is a long path from a lab antibacterial to a clinically useful drug — issues such as stability in the body, toxicity and resistance potential must be resolved."

Next steps

To advance the work, Alkhalaf and Challis are collaborating with synthetic chemist David Lupton (Monash University) to develop a chemical synthesis of pre‑methylenomycin C lactone. Synthetic production would enable larger‑scale studies to identify the compound's bacterial target(s), clarify its mechanism of action, assess effects on human cells, and explore structural modifications to improve potency or pharmacological properties.

Bottom line: The discovery highlights how studying natural biosynthetic pathways can reveal previously hidden molecules with unexpected antibacterial activity. While the results are promising, substantial preclinical work remains before this compound could become a viable antibiotic for clinical use.