Chemoenzymatic routes of improved polyene antifungal agents

Fungal infections are an increasingly serious global health threat, driven by rising antimicrobial resistance (AMR) and a critical lack of new antifungal drugs in development. Currently, treatment relies heavily on Amphotericin B (AmB) and a small group of related polyene natural products. However, the clinical use of these compounds is limited by their poor solubility and significant toxicity. Research has shown that chemical modifications of polyenes like AmB can reduce their toxicity, but traditional synthetic approaches to producing these derivatives are far from ideal. These methods typically involve multiple, low-yielding steps, making them costly, environmentally unfriendly, and difficult to scale. Moreover, they often rely on heavy metals, hazardous reagents, and extensive use of protecting groups—practices that conflict with the principles of green chemistry, including step- and atom-economy. The CERIPA project aims to address these challenges by developing cleaner, more efficient, and sustainable chemoenzymatic approaches to modifying polyenes. Our goal is to generate new derivatives with enhanced antifungal activity, reduced toxicity, and improved solubility. We plan to diversify polyene structures by using a newly discovered family of glycosyltransferases to attach non-native sugar moieties at specific sites. Additionally, we will explore the use of other polyene-modifying enzymes to further tailor the molecular backbone. These newly engineered polyene analogues will undergo rigorous bioactivity and toxicity testing to establish structure–activity relationships (SARs), guiding the rational design of next-generation antifungal agents.