Chemists from the University of Warwick and Monash University have discovered a promising new antibiotic that demonstrates effectiveness against drug-resistant bacterial pathogens, including MRSA and VRE. This is reported by UNN with reference to Phys.org.
Details
Antimicrobial resistance (AMR) is one of the most pressing global health problems, and a new WHO report shows that "too few antibacterial drugs are in development." Most "easily accessible opportunities" have already been found, and limited commercial incentives deter investment in antibiotic discovery.
In a study published in the "Journal of the American Chemical Society," researchers from the Monash Alliance Initiative to Combat Emerging Superbug Threats identified 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.
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Co-author of the study, Professor Greg Challis from the Department of Chemistry at the University of Warwick and the Institute of Biomedicine at Monash University, says: "Methylenomycin A was originally discovered 50 years ago, and although it has been synthesized several times, it seems no one has tested 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 more than 100 times more active against various Gram-positive bacteria than the original antibiotic methylenomycin A.
In particular, it has been shown to be effective against S. aureus and E. faecium, bacterial species responsible for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), respectively.
Co-author of the study, Dr. Lona Alhalaf, Associate Professor at the University of Warwick, adds: "Remarkably, the bacterium that produces methylenomycin A and pre-methylenomycin C lactone — Streptomyces coelicolor — is a model antibiotic-producing species that has been thoroughly studied since the 1950s. The discovery of a new antibiotic in such a familiar organism was a real surprise. It appears that S. coelicolor initially evolved to produce a potent antibiotic (pre-methylenomycin C lactone), but over time converted it into methylenomycin A — a much weaker antibiotic that may play a different role in the bacterium's biology."
Importantly, the researchers were unable to 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" drug for treating Enterococcus infection, so this discovery is particularly promising for VRE, a high-priority WHO pathogen.
Professor Challis continues: "This discovery offers a new paradigm for antibiotic development. By identifying and testing intermediates in pathways to diverse natural compounds, we can find potent new antibiotics with greater resistance to resistance that will help us in the fight against antimicrobial resistance."
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In a coordinated publication earlier this year in the Journal of Organic Chemistry, the Monash-led team, collaborating with the Warwick team, reported a scalable synthesis of pre-methylenomycin-C-lactone, paving the way for further research.
Professor David Lupton from the Department of Chemistry at Monash University, who led the synthesis work, says: "This synthetic route should allow for the creation of a variety of analogues that can be used to investigate the structure-activity relationship and mechanism of action of pre-methylenomycin-lactone C. The Centre for Antimicrobial Resistance Impact at Monash provides us with an excellent platform to advance this promising antimicrobial agent."
With its simple structure, potent activity, difficult profile, and scalable synthesis, pre-methylenomycin-lactone C is a promising new candidate that could potentially help save some of the 1.1 million people who fall victim to antimicrobial resistance each year.
Addition
According to the WHO, antibiotic resistance is developing faster than medical progress — new WHO data show alarming trends, particularly evident at the regional level.