title: Improvement of cyclic decapeptides against plant pathogenic bacteria using a combinatorial chemistry approach.
abstract: Cyclic decapeptides were developed based on the previously reported peptide c(LysLeuLysLeuLysPheLysLeuLysGln). These compounds were active against the economically important plant pathogenic bacteria Erwinia amylovora, Pseudomonas syringae and Xanthomonas vesicatoria. A library of 56 cyclic decapeptides was prepared and screened for antibacterial activity and eukaryotic cytotoxicity, and led to the identification of peptides with improved minimum inhibitory concentration (MIC) against P. syringae (3.1-6.2 microM) and X. vesicatoria (1.6-3.1 microM). Notably, peptides active against E. amylovora (MIC of 12.5-25 microM) were found, constituting the first report of cyclic peptides with activity towards this bacteria. A second library based on the structure c(X(1)X(2)X(3)X(4)LysPheLysLysLeuGln) with X being Lys or Leu yielded peptides with optimized activity profiles. The activity against E. amylovora was further improved (MIC of 6.2-12.5 microM) and the best peptides displayed a low eukaryotic cytotoxicity at concentrations 30-120 times higher than the MIC values. A design of experiments permitted to define rules for high antibacterial activity and low cytotoxicity, being the main rule X(2) not equal X(3), and the secondary rule X(4)=Lys. The best analogs can be considered as good candidates for the development of effective antibacterial agents for use in plant protection.
authors.affiliation: Laboratori d'Innovació en Processos i Productes de Síntesi Orgànica (LIPPSO), Departament de Química, Universitat de Girona, Campus Montilivi, 17071 Girona, Spain.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monroc
authors.forename: Esther
authors.initials: E
authors.lastname: Badosa
authors.forename: Emili
authors.initials: E
authors.lastname: Besalú
authors.forename: Marta
authors.initials: M
authors.lastname: Planas
authors.forename: Eduard
authors.initials: E
authors.lastname: Bardají
authors.forename: Emili
authors.initials: E
authors.lastname: Montesinos
authors.forename: Lidia
authors.initials: L
authors.lastname: Feliu
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D010935:Plant Diseases / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D019151:Peptide Library; D010456:Peptides, Cyclic