title: Structure-activity relationships in ultrashort cationic lipopeptides: the effects of amino acid ring constraint on antibacterial activity.
abstract: Taking a minimalistic approach in efforts to lower the cost for the development of new synthetic antimicrobial peptides, ultrashort cationic lipopeptides were designed to mimic the amphiphilic nature crucial for their activity but with only a very short peptide sequence ligated to a lipidic acid. Nine ultrashort cationic lipopeptides were prepared to study the effects of ring constraint in the amino acid side chain of the peptide component. USCL-PCat1, consisting of only four L-4R-aminoproline residues and acylated with palmitic acid at the N-terminus, was found to populate a polyproline II helical secondary conformation that is stable to different pHs and temperatures using circular dichroism. The synthesized lipopeptides were found to have a micellar structure in water using negative staining transmission electron microscopy. We found that constraining the side chain of the amino acid component is not beneficial to the antimicrobial activity. USCL-Dab1, USCL-Dab3 and USCL-K1 showed promising activity against a panel of laboratory reference and clinically isolated Gram-positive and Gram-negative bacterial strains, some of which are multidrug resistant. No appreciable cytotoxicity against human monocytic THP-1 cells was observed up to concentrations of 20-40 µM for all synthesized compounds. Moreover, all USCLs did not induce the production of either pro-inflammatory cytokines or chemokines up to 40 µM.
authors: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
authors: Ronald
authors: R
authors: Domalaon
authors: Xuan
authors: X
authors: Yang
authors: Joe
authors: J
authors: O'Neil
authors: George G
authors: GG
authors: Zhanel
authors: Neeloffer
authors: N
authors: Mookherjee
authors: Frank
authors: F
authors: Schweizer
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000737:chemistry; D002412:Cations / Q000737:chemistry*; D002460:Cell Line; D002942:Circular Dichroism; D016207:Cytokines / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055666:Lipopeptides / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D002412:Cations; D016207:Cytokines; D055666:Lipopeptides; D010446:Peptide Fragments; D010455:Peptides; D012997:Solvents; D011392:Proline