Exploiting a global regulator for small molecule discovery in Photorhabdus luminescens.
Bacterially produced small molecules demonstrate a remarkable range of structural and functional diversity and include some of our most useful biological probes and therapeutic agents. Annotations of bacterial genomes reveal a large gap between the number of known small molecules and the number of biosynthetic genes/loci that could produce such small molecules, a gap that most likely originates from tight regulatory control by the producing organism. This study coupled a global transcriptional regulator, HexA, to secondary metabolite production in Photorhabdus luminescens, a member of the Gammaproteobacteria that participates in a complex symbiosis with nematode worms and insect larvae. HexA is a LysR-type transcriptional repressor, and knocking it out to create a P. luminescens DeltahexA mutant led to dramatic upregulation of biosynthesized small molecules. Use of this mutant expanded a family of stilbene-derived small molecules, which were known to play important roles in the symbiosis, from three members to at least nine members.
Renee
R
Kontnik
Jason M
JM
Crawford
Jon
J
Clardy
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D001688:Biological Products / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D007313:Insecta / Q000382:microbiology; D007814:Larva / Q000378:metabolism / Q000382:microbiology; D009348:Nematoda / Q000382:microbiology*; D020637:Photorhabdus / Q000235:genetics* / Q000378:metabolism*; D011392:Proline / Q000378:metabolism; D054852:Small Molecule Libraries; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology; D013559:Symbiosis; D037521:Virulence Factors / Q000378:metabolism
D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001688:Biological Products; D004268:DNA-Binding Proteins; C084499:HexA protein, bacteria; D054852:Small Molecule Libraries; D013267:Stilbenes; D037521:Virulence Factors; D011392:Proline