51³Ô¹ÏÍø

Researchers from 51³Ô¹ÏÍø and The University of Manchester have developed a new family of antifungal compounds that could lead to safer and more effective treatments for life-threatening fungal diseases.

Fungal infections are an increasing global health challenge. As resistance to existing treatments grows, the development of new antifungal medicines has struggled to keep pace. Current drugs can be effective but often cause serious side effects because fungal cells share many biological similarities with human cells, making it difficult to target infections selectively.

Published today in , the research from Professor Jason Micklefield's group, based at 51³Ô¹ÏÍø's Molecular Sciences Research Hub, focuses on polyenes, one of the most important classes of antifungal compounds.

Dr Saadia Nasr Mirza, who worked on the project, commented: "The most effective antifungal agent currently available is a polyene molecule called amphotericin, which is produced by soil bacteria. Although amphotericin is very potent, it is highly toxic, so we set out to discover if bacteria can produce different types of polyenes that are safer than amphotericin. We developed a bioinformatics pipeline, which surprisingly showed that many bacterial species have the capability to produce novel polyenes.”

From genome mining to antifungal drug design

Using a genome mining approach, the researchers have developed a promising new way to discover antifungal medicines. They identified bacterial species that produce entirely new polyene compounds, which were shown by nuclear magnetic resonance (NMR) to possess unique molecular structures previously unseen among antifungal agents. 

Beyond discovering new polyene natural products, the researchers investigated the enzymes responsible for producing them. By harnessing these biological catalysts, they created a library of modified polyene derivatives and tested their antifungal activity.

Several of the engineered compounds demonstrated improved antifungal effectiveness, reduced toxicity and better solubility compared with existing molecules. The findings highlight how enzymes can be used to redesign complex medicines through biological processes, avoiding the lengthy and resource-intensive chemical syntheses traditionally required to modify polyene drugs.

Professor Micklefield said: "We were pleased to find that several of the new polyene derivatives were more potent and less toxic than amphotericin and nystatin, which is another important polyene that is also used in the clinic."

A promising candidate emerges

One compound, known as Nys34, stood out during testing. In a mouse model of invasive aspergillosis, a serious fungal infection caused by Aspergillus fumigatus, Nys34 significantly reduced fungal burden without showing overt signs of toxicity.

The researchers also found that Nys34 appears to kill fungal cells through a different mechanism from amphotericin. This could make it particularly valuable against fungal pathogens that have developed resistance to current treatments.

Professor Micklefield added, "Surprisingly, we found that one of the most effective new polyene derivatives, Nys34, has a different mode of action to the widely used amphotericin. Because Nys34 kills fungal cells in a different way, it could prove very useful to combat emerging pathogens that have evolved resistance to amphotericin."

Building the future antifungal pipeline

This enzyme-based platform could have applications far beyond a single drug candidate. Because the approach is potentially scalable and cost-effective, it could provide a powerful route to generating new antifungal medicines and improving existing ones.

As fungal diseases continue to pose a growing threat worldwide, the researchers hope that Nys34 will progress towards clinical development, while the wider platform helps expand the limited pipeline of antifungal treatments available to patients.