Every year, antibiotic-resistant infections kill around 1.1 million people worldwide due to a lack of effective treatments. Faced with this growing health emergency, laboratories are struggling to renew the therapeutic arsenal, hampered by a lack of profitability and an exhaustion of traditional sources for new molecules. However, a joint team from the universities of Warwick (United Kingdom) and Monash (Australia) has just made an unexpected discovery in a well-known field.
By re-examining the production steps of an antibiotic identified since the 1970s, researchers have isolated a forgotten compound with antimicrobial properties a hundred times more powerful. Published in the Journal of the American Chemical Society, their study highlights a promising molecule, pre-methylenomycin C lactone, capable of neutralizing some of the most resistant bacteria, such as Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE), without promoting the appearance of resistance.
A biological discovery made possible by a methodical strategy
The team led by Professor Greg Challis (University of Warwick and Monash University) and Dr Lona Alkhalaf (University of Warwick) did not initially aim to discover a new antibiotic. Their research aimed to understand the biosynthetic mechanism of methylenomycin A. It is an antibiotic produced by Streptomyces coelicolora model bacteria studied since the 1950s. To do this, the researchers targeted a group of genes responsible for the production of this molecule. They are called “biosynthetic clusters”. By selectively deleting some of these genes, they were able to interrupt the synthesis process at different stages.
This type of genetic analysis makes it possible to reveal intermediate compounds — often unstable or ephemeral — not present in the final product. Thanks to this approach, two new molecules were isolated: pre-methylenomycin C And
pre-methylenomycin C lactone. It is the latter which has shown particularly remarkable antibiotic potential.
The fact that this molecule comes from such a widely studied organism, and that it has never been identified before, illustrates the limits of the traditional approach based on the search for new microbes in exotic environments. As Professor Challis notes in a press release, “ it's a lesson. Even well-known model organisms can still reveal little-known bioactive compounds if we explore their metabolism in more detail. “.
This discovery redirects research towards metabolic pathways already mapped, but insufficiently exploited. It suggests that a better understanding of the biosynthetic steps can still lead to solutions to growing antimicrobial resistance.
Unprecedented effectiveness against the most resistant pathogens
Once isolated, the pre-methylenomycin C lactone was subjected to a battery of microbiological tests to evaluate its antimicrobial activity. The results obtained were then impressive. The compound is more than 100 times more active than methylenomycin A against several Gram-positive bacteria, including resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecium (ERV).
© Corre et al., 2025
Comparative effectiveness.
These two pathogens are responsible for serious nosocomial infections that are difficult to treat. MRSA is resistant to methicillin and other beta-lactams. As for VRE, it survives despite the administration of vancomycin, a last resort antibiotic. According to the World Health Organization, these two species are among the most worrying for global public health.
THE pre-methylenomycin C lactone acts at very low concentration, indicating high therapeutic potency. The researchers determined the minimum inhibitory concentration (MIC), or the dose necessary to block bacterial growth. This MIC remained stable throughout the experiments.
Even more remarkable, no resistance was observed after 28 days of continuous exposure to the antibiotic. Even when the experimental conditions were designed to favor the emergence of mutations. This behavior contrasts sharply with many current antibiotics, which lose effectiveness over treatment.
This response profile is crucial for considering clinical use. A molecule that does not favor the selection of resistant mutants thus becomes a major tool in the fight against antibiotic resistance.
A challenge to traditional methods for discovering antibiotics
Since the 1980s, the discovery of new antibiotics has experienced a critical slowdown. Conventional methods, mainly based on the cultivation of microorganisms from extreme environments (rare soils, deep oceans), have not produced the hoped-for results. The development pipeline is now almost empty. What the WHO describes as alarming in the face of the rise in antibiotic resistance.
The strategy adopted by the Warwick–Monash team breaks with this logic. By revisiting the secondary metabolism of already well-characterized bacteria, researchers have revealed the existence of active molecules invisible in standard approaches. This method, based on the targeted disruption of biosynthetic genes, makes it possible to reveal compounds that are not produced in sufficient quantity under natural conditions to be detected.
As Professor Challis explains: “ Microbial biosynthesis is a series of cascade reactions. By blocking certain steps, we highlight active intermediate molecules which do not appear in the classic final products “. This approach proposes a new paradigm for antibiotic discovery: less geographic exploration, more genetic and metabolic exploration.
This methodological repositioning could rehabilitate thousands of microbial strains already stored in laboratory collections around the world. The challenge would be to re-study them with these finer synthetic biology and analytical chemistry tools.
Towards synthetic production and concrete therapeutic applications
To consider a medical application, it is not enough to discover an active molecule. This would obviously be too easy and above all very risky! We must be able to produce it on a large scale, stabilize it, and make it compatible with safe administration in humans. This is precisely the challenge of the collaboration between the chemists from Monash and Warwick.
Professor David Lupton (Monash University) led the development of a method for the chemical synthesis of pre-methylenomycin C lactone. Published simultaneously in the Journal of Organic Chemistrythis approach makes it possible to produce the molecule without resorting to microbial fermentation. The latter often proves unstable and difficult to industrialize. The relatively simple structure of the compound facilitates this synthesis.
This process also opens the way to the manufacture of chemical analogues. Slightly modifying the structure of lactone will allow exploration of its stability, absorption, interaction with human cells and spectrum of activity against other pathogens. Researchers call this the study of structure-activity relationships.
At the same time, preclinical trials are already planned, in particular to determine possible toxicity in cellular and animal models. These tests will verify that the antimicrobial activity is accompanied by a safety profile sufficient to justify clinical development.
The project benefits from the support of the Monash Warwick Alliance for Combatting Emerging Superbug Threats and funding from the British BBSRC. With a promising molecule, a controlled synthesis and a multidisciplinary team, the foundations have been laid to take the steps towards a future usable antibiotic. But the road remains long, and each step must confirm the robustness of this unexpected rediscovery.
With an unwavering passion for local news, Christopher leads our editorial team with integrity and dedication. With over 20 years’ experience, he is the backbone of Wouldsayso, ensuring that we stay true to our mission to inform.
