Tryptophan end-tagging of antimicrobial peptides for increased potency against Pseudomonas aeruginosa |
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Authors: | Mukesh Pasupuleti Anna Chalupka Matthias Mörgelin Artur Schmidtchen Martin Malmsten |
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Institution: | 1. Section of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden;2. Division of Infection Medicine, Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden;3. Department of Pharmacy, Uppsala University, SE-751 23, Uppsala, Sweden |
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Abstract: | BackgroundDue to increasing antibiotics resistance, antimicrobial peptides (AMPs) are receiving increased attention. Pseudomonas aeruginosa is a major pathogen in this context, involved, e.g., in keratitis and wound infections. Novel bactericidal agents against this pathogen are therefore needed.MethodsBactericidal potency was monitored by radial diffusion, viable count, and minimal inhibitory concentration assays, while toxicity was probed by hemolysis. Mechanistic information was obtained from assays on peptide-induced vesicle disruption and lipopolysaccharide binding.ResultsEnd-tagging by hydrophobic amino acids yields increased potency of AMPs against P. aeruginosa, irrespective of bacterial proteinase production. Exemplifying this by two peptides from kininogen, GKHKNKGKKNGKHNGWK and KNKGKKNGKH, potency increased with tag length, correlating to more efficient bacterial wall and vesicle rupture, and to more pronounced P. aeruginosa lipopolysaccharide binding. End-tag effects remained at high electrolyte concentration and in the presence of plasma or anionic macromolecular scavengers. The tagged peptides displayed stability against P. aeruginosa elastase, and were potent ex vivo, both in a contact lens model and in a skin wound model.General significanceEnd-tagging, without need for post-peptide synthesis modification, may be employed to enhance AMP potency against P. aeruginosa at maintained limited toxicity. |
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Keywords: | AMP antimicrobial peptide CFU colony-forming units CF carboxyfluorescein MIC minimal inhibitory concentration assay RDA radial diffusion assay TSB trypticase soy broth VCA viable count analysis |
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