Researchers from Imperial College London and the University of Manchester report a strategy to engineer next-generation antifungals that are both more potent and less toxic than current standards. Published in Nature, the work targets life-threatening fungal infections at a time when drug resistance is rising and new antifungal development has lagged.
The team focused on polyenes, a powerful class of membrane-active compounds widely exemplified by amphotericin. While amphotericin can be effective, its therapeutic window is narrow because fungal cells share key structural features with human cells, increasing the risk of serious side effects.
Using genome mining, the researchers searched bacterial genomes for biosynthetic pathways predicted to produce previously undiscovered polyenes. Instead of relying on traditional trial-and-error discovery, they combined computational prediction with chemical characterization to uncover novel molecular frameworks.
Once candidate molecules were identified, the group used nuclear magnetic resonance (NMR) spectroscopy to resolve the structures of the new polyenes. Each compound displayed a distinct architecture, indicating that microbial biosynthesis can diversify polyene chemistry beyond what is represented in existing antifungal libraries.
To understand and exploit this diversity, the researchers characterized the enzymes responsible for building the molecules and assembled a set of polyene derivatives for functional testing. Central to the approach was enzymatic remodeling, including glycosylation and amidation steps that reshape bioactivity while preserving antifungal potency.
In mouse experiments, several derivatives showed improved antifungal activity accompanied by reduced toxicity and better solubility relative to parent drugs. The most notable candidate, Nys34, reduced fungal burden in a model of invasive aspergillosis caused by Aspergillus fumigatus without substantial signs of toxicity.
The study also highlights a crucial pharmacological point: Nys34 appears to kill fungal cells via a mode of action different from amphotericin. That divergence may help preserve efficacy against emerging pathogens that have evolved resistance to amphotericin.
Beyond efficacy, the platform offers a manufacturing advantage. By using enzymes rather than multi-step chemical synthesis, the researchers propose a cleaner and potentially scalable route to optimized antifungal compounds, with relevance for broader global access.
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h4>Subject of Research: Enzymatic redesign of polyene antifungal agents for safer, more effective therapies
Article Title: Enzymatic glycosylation and amidation reshapes polyene bioactivity
News Publication Date: 29-Jul-2026
Web References: https://www.nature.com/articles/s41586-026-10834-8
References: 10.1038/s41586-026-10834-8
Image Credits: Professor Jason Micklefield
Keywords
Polyene antifungals; genome mining; NMR structure determination; glycosylation; amidation; enzymatic drug design; invasive aspergillosis; antimicrobial resistance
