Synergy and Target Promiscuity Drive Structural Divergence in Bacterial Alkylquinolone Biosynthesis.

TitleSynergy and Target Promiscuity Drive Structural Divergence in Bacterial Alkylquinolone Biosynthesis.
Publication TypeJournal Article
Year of Publication2017
AuthorsWu, Y, Seyedsayamdost, MR
JournalCell Chem Biol
Volume24
Issue12
Pagination1437-1444.e3
Date Published2017 Dec 21
ISSN2451-9448
Abstract

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 bccomplex 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.

DOI10.1016/j.chembiol.2017.08.024
Alternate JournalCell Chem Biol
PubMed ID29033316
PubMed Central IDPMC5741510
Grant ListDP2 AI124786 / AI / NIAID NIH HHS / United States