Antibiotic for drug-resistant bacteria found in plain sight

Chemists from the University of Warwick and Monash University say they have discovered a promising new antibiotic that shows activity against drug-resistant bacterial pathogens. The breakthrough is significant as most of the ‘low-hanging fruit’ has already been found when it comes to antibacterials, and limited commercial incentives deter investment in antibiotic discovery.

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

“Methylenomycin A was originally discovered 50 years ago, and while it has been synthesised several times, no one appears to have tested the synthetic intermediates for antimicrobial activity!” said co-lead author Professor Greg Challis, from the University of Warwick and the Monash Biomedicine Discovery Institute.

“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, pre-methylenomycin C lactone was shown to be over 100 times more active against diverse Gram-positive bacteria than 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.

“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, [so] finding a new antibiotic in such a familiar organism was a real surprise,” said co-lead author Dr Lona Alkhalaf, from the University of Warwick.

“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.

“This discovery suggests a new paradigm for antibiotic discovery,” Challis said. “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 [antimicrobial resistance].”

The next step in the development of the antibiotic will be preclinical testing. In a publication earlier this year in The Journal of Organic Chemistry, a team 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.

“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,” said Monash University’s Professor David Lupton, who led the synthesis work.

On top of this scalable synthesis, pre-methylenomycin C lactone’s simple structure, potent activity and difficult-to-resist profile make it a promising antibiotic candidate that could help to save some of the 1.1 million people who are the victims of AMR every year.

Image credit: University of Warwick (video still).