Scientists engineer less toxic polyenes by adding second sugar and modifying carboxylate
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An international research team has discovered a new enzymatic pathway that introduces two sugar molecules onto polyene antifungal drugs, reducing their toxicity and increasing potency. The modified compounds, accessed via clean fermentation, could yield affordable alternatives to current treatments like amphotericin B. The discovery, reported in Nature on July 29, comes amid a global rise in drug-resistant fungal infections.
Enzymatic Pathway Discovery
Researchers characterized two enzyme families: glycosyltransferases that add a second sugar to the polyene scaffold, and an amidotransferase that replaces the toxic carboxylate group with an alternative functional group. The enzymes were derived from previously unstudied biosynthetic gene clusters of polyenes like selvamicin and mandimycin. The dual modification was achieved through fermentation, yielding a family of novel antifungal compounds.
Enhanced Potency and Safety
The modified polyenes showed significantly increased antifungal activity and reduced toxicity compared to amphotericin B and nystatin A1. The addition of the second sugar improved water solubility, while the carboxylate modification lowered affinity for cholesterol in human cell membranes, decreasing side effects. In vitro tests demonstrated potent activity against a broad spectrum of drug-resistant fungal strains.
Scalable Fermentation Production
Unlike current chemical synthesis methods that are costly and inefficient, the new compounds can be produced through clean fermentation or enzymatic routes. This could dramatically lower manufacturing costs, making treatment more accessible in low-income regions where liposomal amphotericin B remains prohibitively expensive. The process also aligns with green chemistry principles by avoiding toxic solvents and multiple synthetic steps.
What's Next
The research team will next evaluate the modified polyenes in clinical trials to confirm safety and efficacy in humans. It remains unclear how quickly these candidates can progress through regulatory approval and whether they will overcome the toxicity hurdles that have plagued earlier polyenes.
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Scientists engineer less toxic polyenes by adding second sugar and modifying carboxylate
