Synergy and Target Promiscuity Drive Structural Divergence in Bacterial Alkylquinolone Biosynthesis

Microbial natural products are genetically encoded by dedicated biosynthetic gene clusters (BGCs). A given BGC usually produces a family of related compounds that share a core but contain variable substituents. Though common, the reasons underlying this divergent biosynthesis are in general unknown. Herein, we have addressed this issue using the hydroxyalkylquinoline (HAQ) family of natural products synthesized by Burkholderia thailandensis. Investigations into the detailed functions of two analogs show that they act synergistically in inhibiting bacterial growth. One analog is a nanomolar inhibitor of pyrimidine biosynthesis and at the same time disrupts the proton motive force. A second analog inhibits the cytochrome bc₁ complex as well as pyrimidine biogenesis. These results provide a functional rationale for the divergent nature of HAQs. They imply that synergy and target promiscuity are driving forces for the evolution of tailoring enzymes that diversify the products of the HAQ biosynthetic pathway.