Discovery of Aromatic Meroterpenoids with Potent Anti-biofilm Activity and Genome-Guided Identification of Two Prenyltransferases.

Aspergillus fungi are renowned for producing various natural products, including meroterpenoids that show significant bioactivities. In this study, chemical investigation of a newly identified Aspergillus fungus led to the discovery of seven aromatic meroterpenoids, including two new ones designated as pantaromerotin (1) and pantanitrimerotin (2). Pantaromerotin is distinguished by containing a rare pyran ring formed from a prenyl unit, which are not observed in the structurally similar compound stocksiloate. In comparison, pantanitrimerotin harbors a rare cyanide group, which is not found in the previously reported asperterreusine C. In terms of bioactivity, compounds 2-7 exhibited significant biofilm eradication effects. Notably, compound 5 not only inhibited biofilm formation by 60.4% at sub-MIC concentrations but also demonstrated synergistic antimicrobial effects in combination with kanamycin. Furthermore, genome sequencing and in vitro assays enabled us to identify AtUbiA3 and Pan9 as two functional prenyltransferases, which catalyzes the conversion of the coisolated compound 8 to form 5, providing biochemical insights into the biosynthesis. Collectively, our work identifies aromatic meroterpenoids with promising antibiofilm potential and lays a solid foundation for the subsequent elucidation of their biosynthetic pathways.