1. Biosynthesis of the antimicrobial peptide epilancin 15X and its N-terminal lactate
Juan E Velásquez, Xingang Zhang, Wilfred A van der Donk Chem Biol. 2011 Jul 29;18(7):857-67. doi: 10.1016/j.chembiol.2011.05.007.
Lantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial peptides. The recently discovered lantibiotic epilancin 15X produced by Staphylococcus epidermidis 15X154 contains an unusual N-terminal lactate group. To understand its biosynthesis, the epilancin 15X biosynthetic gene cluster was identified. The N-terminal lactate is produced by dehydration of a serine residue in the first position of the core peptide by ElxB, followed by proteolytic removal of the leader peptide by ElxP and hydrolysis of the resulting new N-terminal dehydroalanine. The pyruvate group thus formed is reduced to lactate by an NADPH-dependent oxidoreductase designated ElxO. The enzymatic activity of ElxB, ElxP, and ElxO were investigated in vitro or in vivo and the importance of the N-terminal modification for peptide stability against bacterial aminopeptidases was assessed.
2. Chemical synthesis and biological activity of analogues of the lantibiotic epilancin 15X
Patrick J Knerr, Wilfred A van der Donk J Am Chem Soc. 2012 May 9;134(18):7648-51. doi: 10.1021/ja302435y. Epub 2012 Apr 30.
Lantibiotics are a large family of antibacterial peptide natural products containing multiple post-translational modifications, including the thioether structures lanthionine and methyllanthionine. Efforts to probe structure-activity relationships and engineer improved pharmacological properties have driven the development of new methods to produce non-natural analogues of these compounds. In this study, solid-supported chemical synthesis was used to produce analogues of the potent lantibiotic epilancin 15X, in order to assess the importance of several N-terminal post-translational modifications for biological activity. Surprisingly, substitution of these moieties, including the unusual N-terminal D-lactyl moiety, resulted in relatively small changes in the antimicrobial activity and pore-forming ability of the peptides.
3. Isolation and structural characterization of epilancin 15X, a novel lantibiotic from a clinical strain of Staphylococcus epidermidis
Miquel B Ekkelenkamp, Micha Hanssen, Shang-Te Danny Hsu, Ad de Jong, Dana Milatovic, Jan Verhoef, Nico A J van Nuland FEBS Lett. 2005 Mar 28;579(9):1917-22. doi: 10.1016/j.febslet.2005.01.083.
The potential application of lantibiotics as food-preserving agents and more recently as antibiotics has strongly increased the interest in these antibacterial peptides. Here, we report the elucidation of the primary and three-dimensional structures of the novel lantibiotic epilancin 15X from Staphylococcus epidermidis using high-resolution nuclear magnetic resonance spectroscopy and tandem mass spectrometry. The molecule contains ten post-translationally modified amino acids, three lanthionine ring structures and a hydroxy-propionyl N-terminal moiety. The primary and tertiary structure and the distribution of positive charges are closely similar to the previously identified lantibiotic epilancin K7, most likely indicative of a common mode of action.
