Genome Mining and Heterologous Expression-Guided Discovery of Mangicol Sesterterpenoids with Antimicrobial and Antineuroinflammatory Activities

The accelerating increase in antimicrobial resistance presents serious dangers to global health, food safety, and agricultural productivity. In this study, we explored fungal-derived sesterterpenoids as potential antimicrobial agents, focusing on mangicols biosynthesized by a newly identified bifunctional terpene synthase from Fusarium oxysporum 14005. By combination of genome mining, heterologous pathway reconstitution, and feature-based molecular networking, eight new mangicols featuring epoxy and tetrahydrofuran moieties on their side chains were identified and characterized. Antimicrobial assays revealed that several of these derivatives exhibited potent activity against Ralstonia solanacearum, Staphylococcus aureus, and Streptococcus mutans, with minimum inhibitory concentrations ranging from 6.25 to 25 μM. Furthermore, compounds 3-5 demonstrated significant antineuroinflammatory effects in murine BV2 microglial cells with 50.0, 53.13, and 48.05%, respectively. The results offer mechanistic insights into the biosynthesis and bioactivity of mangicol-type sesterterpenoids and support their potential as novel antimicrobial and anti-inflammatory agents for addressing antimicrobial resistance.