Scientists have found a hidden antibiotic that is 100 times stronger against deadly germs

Antimicrobial resistance (AMR) is one of the most serious threats to global health. The World Health Organization recently warned that there are “very few antibacterials in production” and that easily detectable antibiotics have already been found. Because developing new antibiotics is expensive and offers only limited financial reward, few pharmaceutical companies invest in this vital area.

Discovering a hidden antibiotic intermediate

In a recent paper in Journal of the American Chemical SocietyResearchers from the Monash-Warwick Alliance Initiative to Combat Emerging Microbial Threats report the discovery of a powerful new antibiotic called premethylenomycin C lactone. The compound was “hiding in plain sight” as an intermediate chemical in the natural process that produces the well-known antibiotic methylenomycin A.

Professor Greg Challis, co-lead author from the Department of Chemistry at the University of Warwick and the Biomedical Discovery Institute at Monash University, explained: “Methylinomycin A was originally discovered 50 years ago, and although it has been synthesized many times, no one seems to have tested the synthetic intermediates for antimicrobial activity! By deleting the biosynthesis genes, we have discovered two previously unknown biosynthetic intermediates, both of which are far more effective antibiotics than methylenomycin A itself.”

100x boost in antibacterial power

When tested, one of these intermediates—pre-methylenomycin C lactone—proved to be more than 100 times more active against a range of Gram-positive bacteria than methylenomycin A. It was particularly effective against a range of Gram-positive bacteria. Staphylococcus aureus and Enterococcus faecalisThese are the bacterial species responsible for methicillin resistance Staphylococcus aureus (MRSA) and resistant to vancomycin Enterococci (VRE).

Co-lead author Dr Luna Al-Khalaf, Associate Professor at the University of Warwick, said: “It is striking that the bacteria that synthesize the methylenomycin A lactone and premethylenomycin C – Streptomyces coelicolor — is a typical antibiotic-producing species that has been extensively studied since the 1950s. “Finding a new antibiotic in such a familiar organism was a real surprise.”

She added that it seemed S.coelicolor They may have originally evolved to produce a powerful antibiotic (pre-methylenomycin C lactone), but over time they shifted toward making methylenomycin A, a weaker version that could perform a different biological role.

It is encouraging that the research team found no evidence of bacterial resistance to pre-methylenomycin C lactone in Enterococci Under conditions that typically lead to resistance to vancomycin. Since vancomycin is often a “last resort” treatment for these infections, this finding is a particularly hopeful sign for the treatment of VRE, which the World Health Organization classifies as a high-priority pathogen.

A new direction for antibiotic discovery

Professor Challis noted: “This discovery points to a new paradigm for antibiotic discovery. By identifying and testing intermediates in the pathways leading to diverse natural compounds, we may find powerful new antibiotics with greater resistance that will help us in the fight against antimicrobial resistance.”

The next step in developing the antibiotic will be pre-clinical testing. In a coordinated publication earlier this year in the Journal of Organic Chemistry, a team led by Monash in collaboration with the Warwick team and funded by the Monash-Warwick Alliance Initiative to Combat Threats from Superbacteria reported a scalable synthesis of pre-methylenomycin C lactone, paving the way for further research.

Professor David Lupton, Monash University School of Chemistry who led the synthesis work, says: “This synthetic pathway should enable the creation of diverse analogs that can be used to explore the structure-activity relationship and mechanism of action of the pre-methylenomycin C lactone. The Monash Antimicrobial Resistance Impact Center gives us a great platform to move forward with these promising antimicrobials.”

With its clear chemical structure, strong antibacterial potency, clear resistance conformation, and scalable production process, premethylenomycin C lactone stands out as a promising new candidate. It could ultimately help save many of the estimated 1.1 million lives lost each year due to antimicrobial resistance.