Merochlorins A-D, cyclic meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium-dependent chloroperoxidases.
Meroterpenoids are mixed polyketide-terpenoid natural products with a broad range of biological activities. Herein, we present the structures of four new meroterpenoid antibiotics, merochlorins A-D, produced by the marine bacterium Streptomyces sp. strain CNH-189, which possess novel chemical skeletons unrelated to known bacterial agents. Draft genome sequencing, mutagenesis, and heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin gene cluster that contains two genes encoding rare bacterial vanadium-dependent haloperoxidase (VHPO) genes. Pathway expression of two different fosmid clones that differ largely by the presence or absence of the VHPO gene mcl40 resulted in the differential biosynthesis of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented 15-membered chloronium-induced macrocyclization reaction converting merochlorin D to merochlorin C.
Scripps Institution of Oceanography, University of California, San Diego, California 92093, USA.
Leonard
L
Kaysser
Peter
P
Bernhardt
Sang-Jip
SJ
Nam
Sandra
S
Loesgen
J Graham
JG
Ruby
Peter
P
Skewes-Cox
Paul R
PR
Jensen
William
W
Fenical
Bradley S
BS
Moore
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D002711:Chloride Peroxidase / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial; D008958:Models, Molecular; D005810:Multigene Family; D054830:Sesterterpenes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048372:Streptomyces coelicolor / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D014639:Vanadium / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D054830:Sesterterpenes; C573231:merochlorin A; C576411:merochlorin B; C576412:merochlorin C; C576413:merochlorin D; D014639:Vanadium; D002711:Chloride Peroxidase