Enzyme-Based Platform Yields Novel Polyene Antifungals with Superior Potency and Reduced Toxicity
核心洞察
Scientists at Imperial College London and The University of Manchester used genome mining to discover a new family of polyene antifungal agents published in Nature.
The lead compound Nys34 (搜索) demonstrated reduced fungal burden in a mouse model of invasive aspergillosis (搜索) without substantive signs of toxicity.
Nys34 (搜索) employs a different mode of action than amphotericin (搜索), potentially overcoming resistance in emerging fungal pathogens.
Scientists at Imperial College London and The University of Manchester have developed a new enzyme-based platform capable of generating a novel family of polyene antifungal agents that are more potent and less toxic than existing treatments, according to research published today in Nature. The approach, which leverages genome mining and enzymatic redesign, addresses the growing global threat of drug-resistant fungal infections at a time when the World Health Organisation has underscored the urgency for new antifungal medicines.
The research, led by the Micklefield Lab based at Imperial's Molecular Sciences Research Hub, focused on polyenes — a powerful class of antifungal agents that includes amphotericin (搜索), the most effective antifungal currently available. Despite its potency, amphotericin carries significant toxicity due to the structural similarities between fungal and human cells, which makes it difficult to target infections without harming healthy tissue.
Genome Mining Reveals Untapped Bacterial Potential
The team developed a bioinformatics pipeline to screen bacterial genomes for the capacity to produce novel polyenes. Dr Saadia Nasr Mirza, who worked on the project, explained: "Although amphotericin (搜索) 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."
Using nuclear magnetic resonance (NMR), the researchers determined the structures of the newly discovered polyenes, confirming that each possessed a unique structure distinct from any existing antifungal compounds. They also characterised the enzymes responsible for producing these molecules and generated a library of polyene derivatives for testing.
Nys34 (搜索): A Promising Lead with a Novel Mechanism
Several of the new compounds demonstrated increased antifungal activity, reduced toxicity, and improved solubility compared with the parent drugs. One compound, Nys34 (搜索), showed particularly promising results. In a mouse model of invasive aspergillosis (搜索) — a serious fungal infection caused by Aspergillus fumigatus (搜索) — Nys34 reduced fungal burden without substantive signs of toxicity.
Professor Jason Micklefield, who led the project, noted: "We were pleased to find that several of the new polyene derivatives were more potent and less toxic than amphotericin (搜索) and nystatin, which is another important polyene that is also used in the clinic."
Critically, the team discovered that Nys34 (搜索) operates through a different mode of action than amphotericin (搜索). "Because Nys34 kills fungal cells in a different way, it could prove very useful to combat emerging pathogens that have evolved resistance to amphotericin," Micklefield added.
A Cleaner, Scalable Manufacturing Approach
Polyene antifungal drugs are highly complex molecules, and previous efforts to improve them have typically relied on lengthy chemical synthesis processes that are expensive, inefficient, and can require environmentally harmful reagents. The Micklefield lab's enzyme-based approach circumvents these limitations by producing improved polyenes through cleaner and more efficient biological processes, generating promising drug candidates without complex multi-step chemical manufacturing.
The process is potentially scalable and cost-effective, which could help make improved antifungal treatments more widely available, particularly in lower-income regions where fungal diseases place a substantial burden on public health.
The researchers hope that further development of Nys34 (搜索) could ultimately lead to clinical testing in humans. Beyond Nys34, the enzyme platform provides a powerful new way of generating and refining polyene antifungal compounds that could be used to create additional treatments for a range of fungal diseases, helping to expand the currently limited pipeline of new antifungal medicines.