A new weapon to defeat antibiotic-resistant bacteria has come from soil. Soil bacteria are the key players. They had long been making antimicrobial substances 100 times more potent than existing antibiotics, but no one knew. That is because what the bacteria made to defeat other microbes was not the antimicrobial substance itself, but its precursor.
A team led by Gregory Challis of the department of chemistry at the University of Warwick said it found a new antimicrobial substance in the soil bacterium Streptomyces coelicolor that can defeat antibiotic-resistant bacteria, according to a paper released on the 27th of last month (local time) in the Journal of the American Chemical Society (JACS).
◇A blind watchmaker found in nature
Scientists are looking to nature for answers to the problem of antibiotic-resistant bacteria. Fleming discovered penicillin, the world's first antibiotic, in a mold. Challis' team revisited Streptomyces, a soil bacterium that secretes antimicrobial substances. This bacterium was already found in 1965 to produce methylenomycin A, a natural antibiotic.
As expected, methylenomycin A does not work against today's antibiotic-resistant bacteria. The team analyzed the multistep pathway by which the soil bacterium synthesizes methylenomycin A. They found a mid-pathway compound, premethylenomycin C lactone, with antibacterial activity 100 times stronger than the final product. Even in trace amounts, this substance killed antibiotic-resistant bacteria that are hard to treat. In other words, the intermediate raw material in the manufacturing process had better efficacy than the drug sold by pharmaceutical companies.
Challis told Nature, "Humans tend to assume that evolution perfects the final product, so we expect the final molecule to be the best antibiotic and intermediates to be less potent," adding, "This discovery is a fine example showing that evolution is like a 'blind watchmaker.'"
The Blind Watchmaker is the title of a book by British evolutionary biologist Richard Dawkins. The term rebuts the watchmaker argument advanced by 19th-century theologian William Paley. Paley argued that, just as a watchmaker makes a complex watch, there exists a God who created life, but Dawkins countered that life arose through natural selection, a blind process, like a blind watchmaker accidentally making a watch.
◇Up to 39 million deaths over 25 years
As the misuse and overuse of antibiotics grows serious, resistant bacteria that do not respond to existing drugs are spreading rapidly. If antibiotics do not work, even a small cut can become life-threatening. According to the World Health Organization (WHO), 1.27 million people worldwide died in 2019 after being infected with antibiotic-resistant bacteria. In a report released on the 2nd of last month, WHO warned that if antibiotic resistance is not properly addressed, up to 39 million people could lose their lives over the next 25 years.
The researchers said they expect the findings to lead to the development of new drugs that overcome antibiotic resistance. Gerard Wright of McMaster University in Canada said, "It shows the potential to discover new bioactive molecules in long-established metabolic pathways."
The findings were truly serendipitous. The team began studying the methylenomycin A biosynthetic pathway of Streptomyces in 2006. Enzymes that catalyze chemical reactions are required in metabolic processes. The researchers deleted, one by one, the enzyme genes involved at each step of methylenomycin A synthesis. Through this, in 2010 they identified how the soil bacterium produces methylenomycin A and confirmed several intermediate molecules generated in the process. It is no different from basic research conducted in any microbiology lab in the world.
A study that might have remained only as a paper advanced into a weapon against antibiotic-resistant bacteria thanks to an experiment by a doctoral student in Challis' lab in 2017. The experiment showed that antibacterial potency increased the further back one went along the methylenomycin A biosynthetic pathway. The intermediates defeated Staphylococcus aureus, which causes skin, blood and internal organ infections and which the final product could not block, and Enterococcus faecium, which can cause deadly bloodstream and urinary tract infections.
◇Does not trigger new resistant bacteria
In particular, the minimum concentration of premethylenomycin C lactone needed to kill antibiotic-resistant Staphylococcus aureus was just 1 μg (microgram; 1 μg is one-millionth of a gram) per mL. This is markedly lower than 256 μg for methylenomycin A, the final product. The compound also killed bacteria at much lower doses than vancomycin. Vancomycin is a "last resort" used to treat two types of enterococcal infections.
The researchers also tested whether premethylenomycin C lactone induces antibiotic resistance. That is because once a new antibiotic appears, resistant strains soon emerge. They increased doses of premethylenomycin C lactone in pathogens for 28 days and compared the results with vancomycin dosing.
As expected, bacteria given vancomycin mutated as doses increased and developed resistance. After 28 days, eight times higher doses were needed to suppress pathogen growth. But the amount of premethylenomycin C lactone required to kill bacteria did not change.
The team has already moved into commercialization studies. Together with researchers at Monash University in Australia, they also developed a mass-production method and published it in an international journal in July. The team said it will further study exactly how premethylenomycin C lactone acts on bacteria. Lona Alkhalaf, a co-corresponding author of the paper, said, "We still do not know exactly where this molecule targets," adding, "If we understand the mechanism of action and toxicity, we may design analogs that retain antibacterial power while removing human toxicity."
References
Journal of the American Chemical Society (2025), DOI: https://doi.org/10.1021/jacs.5c12501
Nature (2025), DOI: https://www.nature.com/articles/d41586-025-03218-x#ref-CR2
Journal of Organic Chemistry (2025), DOI: https://doi.org/10.1021/acs.joc.5c01179