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Antimicrobial function of short amidated peptide fragments from the tick-derived OsDef2 defensin.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Farmakognosi, Pharmacognosy)ORCID iD: 0000-0001-9070-6944
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2019 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 25, no 12, article id e3223Article in journal (Refereed) Published
Abstract [en]

Previously Os, a 22 amino acid sequence of a defensin from the soft tick Ornithodoros savignyi, was found to kill Gram-positive and Gram-negative bacteria at low micromolar concentrations. In this study, we evaluated synthetic peptide analogues of Os for antibacterial activity with an aim to identify minimalized active peptide sequences and in so doing obtain a better understanding of the structural requirements for activity. Out of eight partially overlapping sequences of 10 to 12 residues, only Os(3-12) and Os(11-22) exhibit activity when screened against Gram-positive and Gram-negative bacteria. Carboxyamidation of both peptides increased membrane-mediated activity, although carboxyamidation of Os(11-22) negatively impacted on activity against Staphylococcus aureus. The amidated peptides, Os(3-12)NH2 and Os(11-22)NH2 , have minimum bactericidal concentrations of 3.3 μM against Escherichia coli. Killing was reached within 10 minutes for Os(3-12)NH2 and only during the second hour for Os(11-22)NH2 . In an E. coli membrane liposome system, both Os and Os(3-12)NH2 were identified as membrane disrupting while Os(11-22)NH2 was less active, indicating that in addition to membrane permeabilization, other targets may be involved in bacterial killing. In contrast to Os, the membrane disruptive effect of Os(3-12)NH2 did not diminish in the presence of salt. Neither Os nor its amidated derivatives caused human erythrocyte haemolysis. The contrasting killing kinetics and effects of amidation together with structural and liposome leakage data suggest that the 3-12 fragment relies on a membrane disruptive mechanism while the 11-22 fragment involves additional target mechanisms. The salt-resistant potency of Os(3-12)NH2 identifies it as a promising candidate for further development.

Place, publisher, year, edition, pages
2019. Vol. 25, no 12, article id e3223
Keywords [en]
antimicrobial resistance, carboxyamidation, mechanism of action, membrane permeabilization, minimalized peptide, tick defensin
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-401412DOI: 10.1002/psc.3223PubMedID: 31713951OAI: oai:DiVA.org:uu-401412DiVA, id: diva2:1383350
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-02-05Bibliographically approved

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