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Discovery and Characterization of Bicereucin, an Unusual d-Amino Acid-Containing Mixed Two-Component Lantibiotic

Huo, Liujie, van der Donk, Wilfred A.
Journal of the American Chemical Society 2016 v.138 no.16 pp. 5254-5257
Bacillus cereus, Enterococcus, Escherichia coli, amino acids, anti-infective properties, antibiotic resistance, bacteriocins, enzymes, hemolysis, methicillin, methicillin-resistant Staphylococcus aureus, peptides, proteolysis, signal peptide
Lantibiotics are a group of ribosomally synthesized and post-translationally modified peptides (RiPPs) exhibiting antimicrobial activity. They are characterized by the presence of the thioether-containing bisamino acids lanthionine and methyllanthionine. Here, we report a two-component lantibiotic from Bacillus cereus SJ1 with unusual structural features that we named bicereucin. Unlike all previous two-component lantibiotics, only one of the two peptides of bicereucin contains a lanthionine. The second peptide lacks any cysteines but contains several d-amino acids. These are installed by the dehydrogenase BsjJB, the activity of which was successfully reconstituted in vitro. The proteolytic removal of the leader peptide was also performed in vitro. Bicereucin displayed synergistic antimicrobial activities against Gram-positive strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci as well as hemolytic activity. To illustrate the utility of the enzymes, an analog of the d-amino acid containing opioid dermorphin was successfully produced in E. coli by employing the dehydratase BsjM and the dehydrogenase NpnJA.