Breakthrough in Battle Against Superbugs: New Antibiotic Pre-methylenomycin C Lactone Discovered

In a significant advancement against antimicrobial resistance, chemists from the University of Warwick and Monash University have discovered a potent new antibiotic, pre-methylenomycin C lactone. This compound demonstrates over 100 times the efficacy against drug-resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) compared to its predecessor, methylenomycin A. The findings were published in the Journal of the American Chemical Society on October 29, 2025.

Antimicrobial resistance (AMR) poses a critical global health challenge, with the World Health Organization (WHO) reporting that one in six laboratory-confirmed bacterial infections worldwide in 2023 were resistant to antibiotic treatments. Between 2018 and 2023, antibiotic resistance rose in over 40% of the pathogen-antibiotic combinations monitored, with an average annual increase of 5–15%. (who.int)

The research team focused on Streptomyces coelicolor, a bacterium extensively studied since the 1950s for its antibiotic-producing capabilities. By deleting specific biosynthetic genes, they identified two previously unknown intermediates in the biosynthesis of methylenomycin A. One of these intermediates, pre-methylenomycin C lactone, exhibited significantly enhanced antibacterial activity.

Professor Greg Challis, co-lead author from the University of Warwick and Monash University, stated, "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!" (monash.edu)

Dr. Lona Alkhalaf, Assistant Professor at the University of 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." (monash.edu)

The discovery suggests a new paradigm for antibiotic discovery by exploring intermediates in known biosynthetic pathways. Importantly, pre-methylenomycin C lactone showed no emergence of resistance in Enterococcus bacteria under conditions where vancomycin resistance is typically observed, indicating its potential resilience against resistance development. (monash.edu)

The next steps involve pre-clinical testing and scalable synthesis of the compound. Professor David Lupton from Monash University, who led the synthesis work, noted, "This synthetic route should enable the creation of diverse analogues that can be used to probe the structure−activity relationship and mechanism of action for pre-methylenomycin C lactone. The Centre to Impact AMR at Monash gives us a great platform to take this promising antimicrobial forward." (monash.edu)

The discovery of pre-methylenomycin C lactone not only provides a promising new candidate in the battle against drug-resistant bacteria but also underscores the importance of revisiting and exploring known biosynthetic pathways to uncover hidden therapeutic potentials.