ABC Transporter Gene-Informed Prioritization for Discovering MDR-Reversal Terpenoids from Talaromyces sp. G23

Applying an ABC transporter gene-informed prioritization strategy to the soil-derived fungus Talaromyces sp. G23 led to the identification of seven andrastin-type meroterpenoids, including two new compounds, talarodemonoids A (1) and B (2), and five known analogues (4-8), along with one new spongian-type diterpenoid, talarodemonoid C (3). Talarodemonoid A (1) possesses a rare oxetane-containing 6/6/6/4/5 pentacyclic framework, representing the second example of this structural class, and is found for the first time to interconvert with its co-isolated precursor simpterpenoid A (4) via a spontaneous [2+2] cycloaddition reaction. Consistent with the strategy, all compounds exhibit tumor multidrug resistance (MDR) reversal activity, with reversal fold (RF) values ranging from 6.2 to 19.3. Mechanistic studies showed that talarodemonoid B (2) potentially binds to the substrate-binding pocket of ABCB1 (P-gp), with marginal ATPase suppression and no effect on its expression. Moreover, based on the biosynthetic gene cluster (BGC) analysis, a hypothetical biosynthetic pathway for 1 was proposed in this work.