title: Salt-resistant short antimicrobial peptides.
abstract: Antimicrobial peptides (AMPs) are promising leads for the development of antibiotics against drug resistant bacterial pathogens. However, in vivo applications of AMPs remain obscure due to salt and serum mediated inactivation. The high cost of chemical synthesis of AMPs also impedes potential clinical application. Consequently, short AMPs resistant toward salt and serum inactivation are desirable for the development of peptide antibiotics. In this work, we designed a 12-residue amphipathic helical peptide RR12 (R-R-L-I-R-L-I-L-R-L-L-R-amide) and two Trp containing analogs of RR12 namely RR12Wpolar (R-R-L-I-W-L-I-L-R-L-L-R-amide), and RR12Whydro (R-R-L-I-R-L-W-L-R-L-L-R-amide). Designed peptides demonstrated potent antibacterial activity; MIC ranging from 2 to 8 μM, in the presence of sodium chloride (150 mM and 300 mM). Antibacterial activity of these peptides was also detected in the presence of human serum. Designed peptides, in particular RR12 and RR12Whydro, were only poorly hemolytic. As a mode of action; these peptides demonstrated efficient permeabilization of bacterial cell membrane and lysis of cell structure. We further investigated interactions of the designed peptides with lipopolysaccharide (LPS), the major component of the outer membrane permeability barrier of Gram-negative bacteria. Designed peptides adopted helical conformations in complex with LPS. Binding of peptides with LPS has yielded dissociation the aggregated structures of LPS. Collectively, these designed peptides hold ability to be developed for salt-resistant antimicrobial compounds. Most importantly, current work provides insights for designing salt-resistant antimicrobial peptides. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 345-356, 2016.
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551.
authors: Harini
authors: H
authors: Mohanram
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551.
authors: Surajit
authors: S
authors: Bhattacharjya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability; D003470:Culture Media / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D057927:Hydrophobic and Hydrophilic Interactions; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D012965:Sodium Chloride / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D003470:Culture Media; D008070:Lipopolysaccharides; D009842:Oligopeptides; D012965:Sodium Chloride
keywords: LPS-AMP interactions; antimicrobial peptides; lipopolysaccharide; membrane; salt resistant AMPs