[1S05m] 13. Microbial Engineering for Natural Products Synthesis - Part 1

11:30 AM - 12:00 PM JST(2:30 AM - 3:00 AM UTC)

[1MENP-05-KL] Engineering and Re-designing Cryptic Polyene Biosynthetic Gene Cluster for Ergosterol-targeting Antifungals

○Eung-Soo Kim¹ (1. Inha University (Korea))

Keywords:

Polyene Antifungals,Biosynthetic Gene Cluster,Re-designing Pathway,Ergosterol-targeting,Pseudonocardia autotrophica

Polyene macrolides remain among the most effective antifungal chemotypes, but their clinical utility continues to be constrained by intrinsic host toxicity. Leveraging genome mining and biosynthetic analysis of a nystatin-like gene cluster named NPP from Pseudonocardia autotrophica, we developed a modular engineering framework to reshape the NPP biosynthetic pathway toward safer antifungal agents. Through iterative redesign of pathway elements including tailoring enzymes, regulatory components, and glycosylation capacity, we generated multiple polyene variants with altered physicochemical and biological properties. These engineered analogues demonstrated improved antifungal performance and reduced toxicity in preliminary assays, suggesting that rational manipulation of inherent polyene scaffolds can shift the therapeutic balance toward increased selectivity and tolerability. In parallel, we implemented both in vitro and in vivo sugar remodeling to expand the scaffold accessibly and establish a chassis capable of further diversification. Overall, this work highlights cryptic polyene BGCs as fertile platforms for designing the next generation of less toxic antifungal agents.