Researchers from the University of Warwick and Monash University have discovered a way to potentially stop one of the world's most dangerous fungal pathogens in its tracks, not by killing it, but by tricking it into switching off its attack mode.
Fungal infections kill an estimated two million people worldwide every year, yet there are no vaccines and few effective treatments. Researchers from the University of Warwick and Monash University have now shown that a bacterial antibiotic called gladiolin can defuse Candida albicans, one of the leading causes of these life-threatening infections, by forcing it back into a harmless state.
Published in Current Biology, the study is the latest result from the Monash Warwick Alliance's antimicrobial resistance (AMR) research programme, a long-running partnership between the two universities.
Candida albicans normally lives harmlessly in the human body. But in critically ill or immunocompromised patients, and especially on medical devices such as catheters, it can switch into an aggressive, thread-like form called hyphae, which burrows into tissue and forms drug-resistant biofilms. The team found that gladiolin doesn't stop hyphae forming in the first place. Instead, it speeds up how quickly they revert back to the harmless, round yeast form once the fungus starts to run low on glucose, cutting short the window it can do damage.
"The thread-like hyphae of Candida albicans allow the fungus to penetrate and damage human tissue and form drug-resistant biofilms, leading to dangerous infections," said Professor Ana Traven, of the Monash Biomedicine Discovery Institute and co-lead of the Monash Warwick Alliance's AMR programme. "We've discovered that gladiolin effectively switches off this aggressive behaviour, pushing the fungus back into its less harmful state. This gives us a different way to think about controlling fungal infections, not just by killing the fungus, but by disarming it."
The mechanism turns out to be a case of chemical trickery. Gladiolin changes the fungus' metabolism, driving it to burn through the glucose in its environment much faster than usual. Since hyphae growth depends on a steady glucose supply, the fungus effectively runs out of the fuel it needs to stay in its invasive form.
"Since glucose is important for the invasive hyphae to grow, gladiolin tricks Candida to use up its glucose supply more quickly, forcing it to switch back to its less invasive yeast state," said Dr Manasa Bharathwaj, first author on the study.
This new study builds on a 2024 discovery from the same team, which showed gladiolin also dramatically boosts the effectiveness of amphotericin B, one of the world's most important antifungal drugs. Together, the two studies suggest gladiolin could fight fungal infections on two fronts at once: making existing antifungal drugs work harder and switching off the behaviour that makes the fungus dangerous in the first place.
Professor Greg Challis, Monash Warwick Alliance Professor of Sustainable Chemistry at the University of Warwick and Monash University added: "Importantly, our findings suggest that gladiolin could help existing drugs kill dangerous fungal pathogens, including drug-resistant biofilms that can form on medical devices, while potentially allowing lower, less toxic doses of antifungal drugs to be used. This is an exciting example of how interdisciplinary and international collaboration can open up new approaches to antimicrobial resistance."
Gladiolin itself was discovered several years ago as a bacterial antibiotic, but its effects on fungal pathogens had remained poorly understood until now.
"In nature, microbes compete for nutrients and space by producing molecules that are toxic to their microbial neighbours," said Professor Traven. "We can harness these natural 'microbial warfare' molecules to discover new medicines. Penicillin is perhaps the best-known example - a molecule made by a fungus to kill competing bacteria that's become one of the world's most effective antibiotics. We're applying the same principle to gladiolin, exploring whether these naturally occurring bacterial molecules can inspire new ways to treat deadly fungal infections."
Antimicrobial resistance is one of the key challenges the Monash Warwick Alliance's grant funding schemes have addressed. The findings add to a growing body of research emerging from the Alliance's strategic investment in antimicrobial resistance research.
