title: Short antibacterial peptides with significantly reduced hemolytic activity can be identified by a systematic L-to-D exchange scan of their amino acid residues.
abstract: High systemic toxicity of antimicrobial peptides (AMPs) limits their clinical application to the treatment of topical infections; in parenteral systemic application of AMPs the problem of hemolysis is one of the first to be tackled. We now show that the selectivity of lipidated short synthetic AMPs can be optimized substantially by reducing their hemolytic activity without affecting their activity against methicillin resistant Staphylococcus aureus (MRSA). In order to identify the optimized peptides, two sets of 32 diastereomeric H-(D)Arg-WRWRW-(L)Lys(C(O)CnH2n+1)-NH2 (n = 7 or 9) peptides were prepared using a split-split procedure to perform a systematic L-to-D exchange scan on the central WRWRW-fragment. Compared to the all-L C8-lipidated lead sequence, diastereomeric peptides had very similar antibacterial properties, but were over 30 times less hemolytic. We show that the observed hemolysis and antibacterial activity is affected by both differences in lipophilicity of the different peptides and specific combinations of L- and D-amino acid residues. This study identified several peptides that can be used as tools to precisely unravel the origin of hemolysis and thus help to design even further optimized nontoxic very active short antibacterial peptides.
authors.affiliation: Inorganic Chemistry I-Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum , 44801 Bochum, Germany.
authors.forename: H Bauke
authors.initials: HB
authors.lastname: Albada
authors.forename: Pascal
authors.initials: P
authors.lastname: Prochnow
authors.forename: Sandra
authors.initials: S
authors.lastname: Bobersky
authors.forename: Sina
authors.initials: S
authors.lastname: Langklotz
authors.forename: Julia E
authors.initials: JE
authors.lastname: Bandow
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D010455:Peptides