Genome Mining and Heterologous Reconstitution of a PKS-NRPS Gene Cluster from Aspergillus flavipes LY1-5 Affords Structurally Novel Tetronates

TL;DR

Scientists discovered ten new natural products from a fungal gene cluster, revealing unique chemical structures and potential antibacterial properties.

Contribution

The study reports the discovery of ten novel tetronate natural products with unique chemical structures from a heterologously expressed fungal gene cluster.

Findings

Ten new tetronate natural products, talactones A–J, were identified from a fungal PKS-NRPS gene cluster.

Talactone A contains a rare 1,4-thiazepane scaffold formed via a non-enzymatic reaction.

Talactones B and C feature a novel 2,3-dihydrofuro [3,4-b]pyridine-4,5(1H,7H)-dione skeleton formed by intramolecular cyclization.

Abstract

Heterologous expression of silent biosynthetic gene clusters represents a key strategy for the discovery of structurally novel natural products. In this study, we obtained ten new tetronate natural products, designated as talactones A–J (1–10), through heterologous expression of a polyketide synthase–nonribosomal peptide synthetase (PKS-NRPS) gene cluster (tho) from the fungus Aspergillus flavipes LY1-5 in A. nidulans A1145. Their structures were elucidated by comprehensive HR-ESI-MS and NMR analyses. Notably, talactone A (1) contains a rare 1,4-thiazepane scaffold, whereas talactones B (2) and C (3) feature a novel 2,3-dihydrofuro [3,4-b]pyridine-4,5(1H,7H)-dione skeleton. Biosynthetic investigations indicate that the 1,4-thiazepane ring in 1 arises from a non-enzymatic reaction between a tetronate acid and cysteine, while 2 and 3 are derived from 5 and 6, respectively, via spontaneous intramolecular cyclization under acidic conditions. Antibacterial activity assays revealed that compounds 1–3, 9, and 10 exhibit moderate antibacterial effects.

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