Overview
- Imperial College London and the University of Manchester used genome mining to find bacterial biosynthetic clusters and characterized enzymes that add a second sugar and modify a carboxylate on polyenes.
- The team built a library of enzyme-modified polyenes and found many derivatives with higher solubility and stronger antifungal activity than parent drugs.
- A lead compound, Nys34, lowered fungal burden in a mouse model of invasive aspergillosis and showed three- to eightfold lower toxicity than amphotericin B in human cell lines.
- Mice tolerated three repeat doses of Nys34 but showed toxicity after a fourth dose, so the authors say further optimization and safety testing are required before clinical development.
- The study, published in Nature, positions enzymatic or fermentation production as a potentially greener, more scalable route than long multistep chemical synthesis and flags mechanism-of-action studies and manufacturing evaluation as next steps.