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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Bactericidal Activity of Small Beta-PeptidomimeticsTerkel Hansen, Dominik Ausbacher, Martina Havelkova, andMorten B. Strøm *Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, 9018,Tromsø, Norway; *Corresponding author, e-mail: morten.strom@uit.noIntroductionThe number of causalities reported in the US by methicillin resistant Staphylococcusaureus (MRSA) infections is currently higher than the number of both HIV/AIDS andtuberculosis together; hence the need for novel antimicrobial agents is urgent [1,2].Cationic antimicrobial peptides (AMP’s) have since their discovery during the 1980’s beenheavily investigated for their antimicrobial properties. AMP’s show a unique mode ofaction by targeting the bacterial cytoplasmic membrane in a non-receptor specific manner,and thereby have a much lower risk of inducing resistance compared to conventionalantimicrobial drugs [3-5].A pharmacophore model for short AMP’s was reported in 2003. In this model activityagainst both E. coli and S. aureus necessitates an amphipathic peptide with a net positivecharge of +2 [6]. To obtain antimicrobial activity against the Gram-negative bacterium E.coli three bulky/lipophilic groups is also a necessity, whereas for activity against the Grampositivebacteria Staphylococcus aureus, MRSA and methicillin resistant Staphylococcusepidermidis (MRSE), only two bulky/lipophilic groups are needed [6].The objective of the current project was to investigate if a scaffold based on an achirallipophilic 3-amino-2,2-disubstituted propionic acid (beta 2,2 -amino acid) coupled to aC-terminal amidated L-arginine residue could confine all the elements of the pharmacophoremodel for anti-staphylococcal activity. The minimal inhibitory concentration(MIC) of the compounds was determined against S. aureus, MRSA, MRSE and E. coli. Atoxicity assessment was performed using human erythrocytes by measuring the hemolyticactivity of the beta-peptidomimetics. Plating of treated bacterium suspensions at differenttime intervals and at different concentrations was used to investigate if the main mechanismof action was bactericidal or bacteriostatic.Results and DiscussionSynthesis:The beta-peptidomimetics were prepared in a seven-step synthesis in which only the threeintermediates shown in Scheme 1 were isolated, as previously reported by our group [7].The total yields for synthesis of the crude Boc-beta 2,2 -amino acids (3a-n) ranged thereforefrom 30-71%, depending on the bulkiness of the lipophilic side-chains. For detailsregarding structures and synthesis, see Hansen, et al [7].Scheme 1. Overview of synthesis.264