New antibiotic for drug-resistant bacteria found hiding in plain sight

Chemists from the University of Warwick and Monash University have discovered a promising new antibiotic that shows activity against drug-resistant bacterial pathogens, including MRSA and VRE

Antimicrobial resistance (AMR) is one of the world’s most urgent health challenges, with the WHO’s new report showing there are ‘too few antibacterials in the pipeline’. Most of the ‘low-hanging fruit’ has already been found, and the limited commercial incentives deter investment in antibiotic discovery.

In a new study published in the Journal of the American Chemical Society, researchers from the Monash Warwick Alliance Combatting Emerging Superbug Threats Initiative have discovered a promising new antibiotic - pre-methylenomycin C lactone. The newly discovered antibiotic was ‘hiding in plain sight’ — as an intermediate chemical in the natural process that produces the well-known antibiotic methylenomycin A.

Co-lead author of the study, Professor Greg Challis, in the Department of Chemistry at the University of Warwick, and Biomedicine Discovery Institute at Monash University says: “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.”

When tested for antimicrobial activity, one of the intermediates, pre-methylenomycin C lactone, was shown to be over 100 times more active against diverse Gram-positive bacteria than the original antibiotic methylenomycin A. Specifically, it was shown to be effective against S. aureus and E. faecium, the bacterial species behind Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) respectively.

Co-lead author Dr. Lona Alkhalaf, Assistant Professor, University of Warwick adds: “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.”

“It looks like S. coelicolor originally evolved to produce a powerful antibiotic (pre-methylenomycin C lactone), but over time has changed it into methylenomycin A — a much weaker antibiotic that may play a different role in the bacterium’s biology.”

Importantly, the researchers could not detect any emergence of resistance to pre-methylenomycin C lactone in Enterococcus bacteria under conditions where vancomycin resistance is observed. Vancomycin is a “last line” treatment for Enterococcus infection, so this finding is especially promising for VRE, a WHO High Priority Pathogen.

Professor Challis continues: “This discovery suggests a new paradigm for antibiotic discovery. 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.”

The next step in the development of 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 collaborating with the Warwick team and funded by the Monash Warwick Alliance Combatting Emerging Superbug Threats initiative reported a scalable synthesis of pre-methylenomycin C lactone, paving the way for further research.

Professor David Lupton, School of Chemistry, Monash University who led the synthesis work says: “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.”

With its simple structure, potent activity, difficult to resist profile, and scalable synthesis, pre-methylenomycin C lactone represents a promising new candidate that could potentially help to save some of the 1.1 million people who are the victims of AMR every year.

ENDS

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About the University of Warwick

Founded in 1965, the University of Warwick is a world-leading institution known for its commitment to era-defining innovation across research and education. A connected ecosystem of staff, students and alumni, the University fosters transformative learning, interdisciplinary collaboration, and bold industry partnerships across state-of-the-art facilities in the UK and global satellite hubs. Here, spirited thinkers push boundaries, experiment, and challenge conventions to create a better world.

About Monash University

Spanning six countries across the Indo-Pacific and Europe, Monash University maintains partnerships with more than 200 universities in over 40 nations. Monash fosters a community of more than 95,000 students and 20,000 staff, celebrating diversity and inclusion. Monash drives research and initiatives that address urgent global challenges. For further insights into Monash's International Portfolio, visit monash.edu/international

About the Monash Warwick Alliance
In 2012 Monash University and The University of Warwick embarked on a ground-breaking partnership, the Monash Warwick Alliance (MWA), a pioneering model for international collaboration woven into the very fabric of both institutions.

Founded on shared principles of academic excellence and social impact, both universities had risen to international prominence through world-class research, a commitment to providing an exceptional educational offering, and a dedication to addressing complex challenges. The Alliance emerged as a natural progression, harnessing and enhancing these combined strengths to forge a unique synergy.

The Alliance was established to promote and develop the excellent collaboration between researchers, educators, students, and professional staff, and harness our collective strengths to empower research and education activities.