title: Design, synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues.
abstract: Class IIa bacteriocins are potent antimicrobial peptides produced by lactic acid bacteria to destroy competing microorganisms. The N-terminal domain of these peptides consists of a conserved YGNGV sequence and a disulphide bond. The YGNGV motif is essential for activity, whereas, the two cysteines involved in the disulphide bond can be replaced with hydrophobic residues. The C-terminal region has variable sequences, and folds into a conserved amphipathic α-helical structure. To elucidate the structure-activity relationship in the N-terminal domain of these peptides, three analogues (1-3) of a class IIa bacteriocin, Leucocin A (LeuA), were designed and synthesized by replacing the N-terminal β-sheet residues of the native peptide with shorter β-turn motifs. Such replacement abolished the antibacterial activity in the analogues, however, analogue 1 was able to competitively inhibit the activity of native LeuA. Native LeuA (37-mer) was synthesized using native chemical ligation method in high yield. Solution conformation study using circular dichroism spectroscopy and molecular dynamics simulations suggested that the C-terminal region of analogue 1 adopts helical folding as found in LeuA, while the N-terminal region did not fold into β-sheet conformation. These structure-activity studies highlight the role of proper folding and complete sequence in the activity of class IIa bacteriocins.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Krishna Chaitanya
authors.initials: KC
authors.lastname: Bodapati
authors.forename: Rania
authors.initials: R
authors.lastname: Soudy
authors.forename: Hashem
authors.initials: H
authors.lastname: Etayash
authors.forename: Michael
authors.initials: M
authors.lastname: Stiles
authors.forename: Kamaljit
authors.initials: K
authors.lastname: Kaur
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001430:Bacteriocins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D056568:Carnobacteriaceae / Q000187:drug effects; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects; D008088:Listeriosis / Q000188:drug therapy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; C071726:leucocin A-UAL 187