Identification of new bisabosqual-type meroterpenoids reveals non-enzymatic conversion of bisabosquals into -bisabosquals.

Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a,9,9a-hexahydro-1-benzofuro[4,3,2-]chromene skeleton (6/6/6/5 ring system) or its -C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and -bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272β is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.