Antimicrobial leucocin analogues with a disulfide bridge replaced by a carbocycle or by noncovalent interactions of allyl glycine residues.
The type IIa bacteriocins are antimicrobial peptides isolated from lactic acid bacteria that act as food preservation agents and have nanomolar activity against pathogens such as Listeria monocytogenes. Previous reports with mutant bacteriocins indicate that the conserved disulfide bridge between cysteine residues 9 and 14 in bacteriocins such as leucocin A (1) is critical for antibiotic properties, which are mediated by target membrane receptor proteins belonging to the mannose phosphotransferase (mpt) system. To examine whether the disulfide can be replaced by an olefin moiety, [9,14]-dicarba leucocin A (4) was made by on-resin ring closing metathesis of allyl glycine residues using a new protocol suitable for larger hydrophobic peptides. Carbocyclic analogue 4 still displays nanomolar activity but is about 10-fold less potent than 1. Surprisingly, the acyclic [9,14]-diallyl leucocin A (5) displays even higher antibiotic activity than 4 and is as effective as the parent, leucocin A (1). We attribute this activity to hydrophobic intermolecular interactions of the diallyl side chains of the acyclic bacteriocin 5 that assist realization of the correct conformation at the receptor active site. Such substitutions in other systems may allow linear acyclic peptides to mimic the biological activity of natural disulfide ring-containing parents.
Derksen
Darren J
DJ
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Stymiest
Jake L
JL
Vederas
John C
JC
D000498:Allyl Compounds / Q000737:chemistry*; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D001430:Bacteriocins / Q000138:chemical synthesis / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D005998:Glycine / Q000737:chemistry*; D006844:Hydrocarbons, Cyclic / Q000737:chemistry*; D008956:Models, Chemical; D008969:Molecular Sequence Data
D000498:Allyl Compounds; D000890:Anti-Infective Agents; D001430:Bacteriocins; D004220:Disulfides; D006844:Hydrocarbons, Cyclic; C071726:leucocin A-UAL 187; D005998:Glycine