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.