Researchers from the University of Warwick and Monash University report that pre-methylenomycin C lactone—an overlooked biosynthetic intermediate from Streptomyces coelicolor—shows more than a 100-fold increase in activity over methylenomycin A against Gram‑positive pathogens, including those behind MRSA and VRE. The finding adds momentum to efforts to tackle antimicrobial resistance, which was directly linked to an estimated 1.27 million deaths in 2019.
In a study published in the Journal of the American Chemical Society in October 2025, a Warwick–Monash team identified pre-methylenomycin C lactone as a potent intermediate in the biosynthetic pathway of methylenomycin A, an antibiotic first characterized in the 1970s. By deleting specific biosynthetic genes in Streptomyces coelicolor—a model antibiotic‑producing bacterium extensively studied since the 1950s—the researchers revealed two previously unknown intermediates that outperformed methylenomycin A.
Laboratory tests showed that pre-methylenomycin C lactone was more than 100 times as active as methylenomycin A against diverse Gram‑positive bacteria, notably Staphylococcus aureus and Enterococcus faecium, the species associated with MRSA and VRE. The team also reported that Enterococcus did not develop resistance to the compound under conditions that typically induce resistance to vancomycin, a last‑line therapy for serious infections.
Professor Greg Challis, co‑lead author from the University of Warwick and Monash University, said: "Methylenomycin A was originally discovered 50 years ago and while it has been synthesized several times, no‑one appears to have tested the synthetic intermediates for antimicrobial activity! By deleting biosynthetic genes, we discovered two previously unknown biosynthetic intermediates, both of which are much more potent antibiotics than methylenomycin A itself."
Dr. Lona Alkhalaf, assistant professor at Warwick, added: "Remarkably, the bacterium that makes methylenomycin A and pre‑methylenomycin C lactone—Streptomyces coelicolor—is a model antibiotic‑producing species that's been studied extensively since the 1950s. Finding a new antibiotic in such a familiar organism was a real surprise."
Why it matters
Global health agencies have warned that the antibiotic pipeline remains thin even as resistance rises. VRE is listed by the World Health Organization as a high‑priority pathogen, underscoring the need for new treatments with durable activity.
Next steps and synthesis advance
The researchers say pre‑clinical evaluation is the next step. In complementary work reported in the Journal of Organic Chemistry in 2025, a Monash‑led team described a scalable route to pre‑methylenomycin C lactone, enabling the creation of analogues to probe structure–activity relationships and mechanism. As Professor David Lupton of Monash noted, the route should facilitate building diverse analogues to better understand and optimize the molecule’s antibacterial properties.
Taken together, the studies highlight a strategy for antibiotic discovery: systematically testing intermediates in natural‑product pathways that may have been overlooked, even in well‑studied organisms.
