Scientists from Imperial College London and The University of Manchester have developed a new generation of antifungal drugs that could offer safer and more effective treatment options for life-threatening fungal infections.
The research introduces a new family of polyene-based compounds that outperformed some existing therapies in preclinical testing.
Published in Nature, the study found that several newly engineered antifungal compounds demonstrated greater potency, reduced toxicity and improved solubility compared with widely used antifungal medicines.
One lead candidate, known as Nys34, successfully reduced fungal infection in mice without causing significant signs of toxicity.
The findings represent a potential breakthrough in the search for new antifungal drugs at a time when fungal infections are becoming more difficult to treat due to increasing drug resistance and a limited pipeline of new medicines.
Researchers also developed a scalable enzyme-based production platform that could simplify manufacturing and improve global access to future treatments.
Growing demand for better antifungal drugs
Fungal diseases are an increasing public health concern worldwide, particularly among people with weakened immune systems. At the same time, resistance to existing therapies continues to rise, reducing the effectiveness of current treatment options.
Developing new antifungal drugs has historically been challenging because fungal cells share many biological characteristics with human cells.
This makes it difficult to eliminate infections without damaging healthy tissue, leaving many of the most effective medicines associated with significant side effects.
Recent warnings from the World Health Organization (WHO) have highlighted the urgent need for new antifungal therapies capable of overcoming resistance while offering improved safety.
Discovering new compounds through genome mining
The research team focused on polyenes, a long-established class of antifungal drugs that includes amphotericin and nystatin. Although highly effective, these medicines are often limited by toxicity, particularly amphotericin, which is widely used to treat severe fungal infections.
Using a genome mining approach, the researchers identified bacterial species capable of producing previously undiscovered polyene antifungal compounds.
This computational strategy revealed that numerous bacterial species possess the genetic potential to create antifungal molecules that had never before been characterised.
The team then used nuclear magnetic resonance (NMR) analysis to determine the molecular structures of the newly discovered compounds. Each displayed structural features distinct from existing antifungal agents, providing fresh opportunities for drug development.
Enzyme platform produces safer drug candidates
Beyond discovering new molecules, the researchers investigated the enzymes responsible for producing them and used these biological tools to generate an expanded library of polyene derivatives.
Testing showed that several of these redesigned compounds exhibited stronger antifungal activity while also reducing toxicity and improving water solubility.
The enzyme-guided approach enabled researchers to modify complex natural products through biological processes rather than relying on lengthy chemical synthesis.
Traditional methods of improving polyene drugs typically involve complex, multi-step manufacturing processes that are expensive and often require environmentally harmful chemical reagents.
The newly developed enzyme platform offers a cleaner, more efficient alternative that could accelerate the creation of improved antifungal drugs.
Nys34 emerges as a promising lead candidate
Among the newly developed compounds, Nys34 delivered the strongest overall performance during preclinical evaluation.
In a mouse model of invasive aspergillosis, a serious infection caused by Aspergillus fumigatus, the compound significantly reduced fungal burden while showing no substantial signs of toxicity.
Researchers also found that Nys34 attacks fungal cells through a different biological mechanism than amphotericin, raising the possibility that it could remain effective against fungal strains that have developed resistance to current treatments.
Supporting future treatment development
The researchers believe their enzyme engineering platform could help expand the limited pipeline of new antifungal drugs by enabling faster discovery and optimisation of additional polyene compounds.
Because the production process is designed to be scalable and cost-effective, it could also improve access to advanced antifungal medicines in lower-income countries, where fungal diseases place a particularly heavy burden on healthcare systems.
Future research will focus on further developing Nys34 and other promising compounds, with the long-term goal of progressing the most successful candidates towards clinical testing in humans.
If successful, the platform could provide a new route for developing safer, more effective antifungal drugs capable of addressing one of the world’s fastest-growing infectious disease challenges.
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