Back in 2006, a team of chemists began a project to understand how soil bacteria Streptomyces coelicolor produces the antibiotic methylenomycin A. Little did they know at the time that their research would lead to the discovery of an entirely new antibiotic that tests showed was 100 times more effective than the original at fighting drug-resistant superbugs such as methicillin-resistant Staphylococcus aureus (MRSA).
“This was truly a serendipitous discovery,” co-lead author Professor Greg Challis of the Department of Chemistry at the University of Warwick, UK, and the Biomedical Discovery Institute, Monash University, Australia, said in an interview. press release. The team's work has since been described in the Journal of the American Chemical Society.
“This discovery offers a new paradigm for antibiotic discovery. By identifying and testing intermediates along the path to various natural compounds, we can find powerful new antibiotics with greater resistance to resistance that will help us fight [antimicrobial resistance]Challis explained.
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Antibiotic hiding in plain sight
Initially, researchers honed in on the process by which Streptomyces coelicolor produces methylenomycin A by analyzing each step in detail and methodically removing genes in the enzymes involved to determine the impact it had on methylenomycin production.
During this process, they discovered various intermediate molecules that were later tested for antimicrobial activity.
“Methylenomycin A was originally discovered 50 years ago, and although it has been synthesized several times, no one seems to have tested the synthetic intermediates for antimicrobial activity!” Challis said.
In these tests, the pre-methylenomycin C lactone intermediate was found to be two orders of magnitude (or 100 times) more active against Gram-positive bacteria than methylenomycin A. Importantly, it was effective against two bacteria (Staphylococcus aureus And Enterococcus faecium) responsible for MRSA and vancomycin-resistant Enterococcus (FRE).
Co-lead author Dr Lona Alkhalaf, an associate professor at the University of Warwick, called the discovery of a new antibiotic from a bacterium that had been studied since the 1950s “a real surprise”.
According to Alkhalaf, the research could go in two directions. The first is to study its potential as an antibiotic and determine whether it is a viable drug candidate. Second, study the activity of the premethylenomycin C lactone in more detail to see if potential antibiotics can be identified from other intermediates.
“This gives us incentive to potentially take a completely new line of research, in which we could start looking more at the intermediates of other antibiotics And [see] if they have this improved activity,” Alkhalaf said.
Christopher Schofield, a professor of chemistry at the University of Oxford in the UK who was not involved in the study, emphasized the importance of the work, explaining that molecules such as methylenomycin are important antibiotics that “may have been understudied recently compared to larger, often easier to study, natural products.”
“Importantly, the authors show that two biosynthetic intermediates are substantially more active than methylenomycin A itself,” Schofield said.
Combating antimicrobial resistance
Not so long ago, a small cut could be life-threatening, and there were no effective treatments for blood poisoning, pneumonia, gonorrhea and many other ailments. The very first true antibiotic was not discovered until the 1920s, when Alexander Fleming discovered penicillin by chance (as did Challis and his colleagues). Even then, it did not become widely available until the 1940s.
Less than a century later, antimicrobial resistance has become one of the most serious public health threats. It was directly responsible for more than a million deaths worldwide in 2019, according to the World Health Organization (WHO).
Last month, the WHO published a report warning that “too few antibacterial drugs are in development” due to the twin crises of “shortages and lack of innovation.” Although premethylenomycin C lactone is still a long way from reaching the market (next steps include preclinical testing), the researchers describe it as “a promising starting point for the development of new antibiotics to combat antimicrobial resistance.”
“What's nice and exciting is to see that in systems where we think we understand everything, we're still making new discoveries and it's not over yet,” said co-author Professor Christophe Corr from the Department of Life Sciences at the University of Warwick. “I am sure there is still much to be understood and discovered.”
This article does not contain medical advice and should be used for informational purposes only.
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