Genome Engineering for Enhanced Production and Derivative Development of Di-sugar Polyene Compounds

초록

Polyene antibiotics are clinically important antifungal agents produced predominantly by soil-dwelling actinomycetes. Although compounds such as nystatin and amphotericin are widely used, their therapeutic application is limited due to severe hemolytic toxicity. This highlights the need for novel polyene antibiotics with improved safety and potent antifungal efficacy. Previously, we developed NPP B1, a novel polyene exhibiting reduced toxicity comparable to nystatin and antifungal activity comparable to amphotericin. However, its low production yield posed a significant limitation for further development. In this study, we enhanced NPP B1 production through a combination of strategies: iterative mutagenesis for gene overexpression, targeted overexpression of a key regulatory gene, and heterologous expression in an alternative microbial host. Additionally, using CRISPR-Cas9 genome editing, we engineered a series of novel NPP B1 derivatives with improved antifungal activity and reduced toxicity. These findings underscore the potential of NPP B1 and its derivatives as promising candidates for the development of next-generation polyene antifungal therapeutics.