Aggregicyclins Shed Light on Type II Polyketide Biosynthesis in Myxococcota.

Polycyclic bacterial specialized metabolites such as anthraquinones, angucyclines, and tetracyclines are predominantly produced by type II polyketide synthase (PKS) systems and represent an important source of antibiotics and anticancer agents. While type II PKS pathways are well characterized in Gram-positive bacteria, their biosynthetic potential in Gram-negative bacteria remains largely unexplored. Here, we report the discovery and activation of a cryptic type II PKS biosynthetic gene cluster from the myxobacterium Aggregicoccus edonensis MCy10622. Using a rapid PCR-based cloning and promoter-exchange strategy, the compact gene cluster was heterologously expressed in Myxococcus xanthus DK1622, leading to the production of two previously unknown specialized metabolites, aggregicyclin and oxyaggregicyclin. Structural analysis revealed an unusual polycyclic scaffold featuring a wide-spanning biaryl ether linkage. Biosynthetic analysis supports an early diversification event during first-ring cyclization as the basis for product divergence. Aggregicyclin exhibits antibacterial activity against Staphylococcus aureus and cytotoxicity against human cancer cells. Together, these findings expand the current knowledge of type II polyketide biosynthesis in Gram-negative bacteria.