The discovery was a ‘surprise’, says study co-author Gregory Challis, a chemical biologist at the University of Warwick in Coventry, UK. “As humans, we anticipate that evolution perfects the end product, and so you’d expect the final molecule to be the best antibiotic, and the intermediates to be less potent,” he says. But the finding “is a great example of what a ‘blind watchmaker’ evolution is. And it’s a good way of exemplifying it in a very molecular way,” adds Challis.

Antimicrobial resistance is a growing threat, projected to cause 39 million deaths worldwide over the next 25 years. Researchers say that the discovery of a potent antimicrobial compound might lead to fresh drugs to tackle resistance.

The work underscores “the potential of such studies to identify new bioactive chemical scaffolds from ‘old’ pathways”, says Gerard Wright, a biochemist at McMaster University in Hamilton, Canada.

Accidental discovery

In 2006, Challis and his colleagues began studying the molecular pathway through which Streptomyces coelicolor produces methylenomycin A. To do this, they deleted the genes encoding enzymes involved in each step, one by one. Their work built on earlier efforts in 2002 to sequence the bacterium’s genome4.

By 2010, the team had mapped the mechanism that the bacterium used to make methylenomycin A and identified several intermediate molecules that it produced along the way.

“We were just doing very fundamental blue-sky research,” says Challis. “We discovered these intermediates, and we left them for a while because we didn’t quite know what to do with them.”

It was several years later — around 2017 — that a PhD student at Challis’s laboratory tested these intermediate molecules for antimicrobial activity.

These tests revealed that two molecules, including premethylenomycin C lactone, were much more effective than methylenomycin A at targeting seven strains of Gram-positive bacteria, including Staphylococcus aureus, which infects skin, blood and internal organs, and Enterococcus faecium, which can cause deadly bloodstream and urinary infections.

The lowest concentration of premethylenomycin C lactone needed to kill drug-resistant strains of Staphylococcus aureus was just 1 microgram per millilitre, compared with 256 micrograms per millilitre of methylenomycin A. The compound could also kill bacteria at much smaller doses than those needed for vancomycin, a ‘last line’ antibiotic used to treat infections caused by two Enterococcus faecium strains, to be effective.

The team then tested whether E. faecium could develop resistance to the newly discovered antibiotic. They treated bacteria with increasing concentrations of premethylenomycin C lactone for 28 days and compared the results with those of vancomycin.

Vancomycin-treated bacteria mutated and developed resistance — after 28 days, eight times higher doses of the drug were needed to stop their growth. But the amount of premethylenomycin C lactone that was effective did not change over the course of the experiment, suggesting that E. faecium does not easily develop resistance to the new molecule.

The work “is a lovely example of how basic research on a chemically interesting antibiotic can have unexpected benefit”, says Christopher Schofield, a chemist who studies antibacterial resistance at the University of Oxford, UK.

Future directions

Earlier this year, another research group collaborated with Challis’s team to develop a cost-effective way to synthesize the antibiotic using commercial materials5, which might help to produce it at scale.

But the researchers first plan to explore how exactly the molecule works against bacteria. “We still don’t really know where it targets. We think it targets the cell wall in some way,” says study co-author Lona Alkhalaf, a chemical biologist at the University of Warwick.

Challis adds that further research is needed to test the molecule’s toxicity in mammalian cells. Understanding the mechanism of action and toxicity could allow researchers to engineer analogues “where we retain the activity against the target in the bacteria, but we engineer out any other activities that might be causing toxicity in humans”, he says.