AUTHOR=Shin Daniel , Byun Woong Sub , Moon Kyuho , Kwon Yun , Bae Munhyung , Um Soohyun , Lee Sang Kook , Oh Dong-Chan 

TITLE=Coculture of Marine Streptomyces sp. With Bacillus sp. Produces a New Piperazic Acid-Bearing Cyclic Peptide

JOURNAL=Frontiers in Chemistry

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2018.00498

DOI=10.3389/fchem.2018.00498

ISSN=2296-2646

ABSTRACT=<p>Microbial culture conditions in the laboratory, which conventionally involve the cultivation of one strain in one culture vessel, are vastly different from natural microbial environments. Even though perfectly mimicking natural microbial interactions is virtually impossible, the cocultivation of multiple microbial strains is a reasonable strategy to induce the production of secondary metabolites, which enables the discovery of new bioactive natural products. Our coculture of marine <italic>Streptomyces</italic> and <italic>Bacillus</italic> strains isolated together from an intertidal mudflat led to discover a new metabolite, dentigerumycin E (<bold>1</bold>). Dentigerumycin E was determined to be a new cyclic hexapeptide incorporating three piperazic acids, <italic>N</italic>-OH-Thr, <italic>N</italic>-OH-Gly, β-OH-Leu, and a pyran-bearing polyketide acyl chain mainly by analysis of its NMR and MS spectroscopic data. The putative PKS-NRPS biosynthetic gene cluster for dentigerumycin E was found in the <italic>Streptomyces</italic> strain, providing clear evidence that this cyclic peptide is produced by the <italic>Streptomyces</italic> strain. The absolute configuration of dentigerumycin E was established based on the advanced Marfey's method, ROESY NMR correlations, and analysis of the amino acid sequence of the ketoreductase domain in the biosynthetic gene cluster. In biological evaluation of dentigerumycin E (<bold>1</bold>) and its chemical derivatives [2-<italic>N</italic>,16-<italic>N</italic>-deoxydenteigerumycin E (<bold>2</bold>) and dentigerumycin methyl ester (<bold>3</bold>)], only dentigerumycin E exhibited antiproliferative and antimetastatic activities against human cancer cells, indicating that <italic>N</italic>-OH and carboxylic acid functional groups are essential for the biological activity.</p>