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Antimicrobial activity of enantiomeric pairs of cationic cyclic lipopeptides against Staphylococcus aureus
Stockholm University, Faculty of Science, Department of Neurochemistry. (Anders Undén)
Stockholm University, Faculty of Science, Department of Neurochemistry. (Anders Undén)ORCID iD: 0000-0003-1003-6472
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have previously shown that the peptides cyclo[D-Tle-D-Lys-D-Tle-L-Ala-D-Tle-L-Ala-D-Tle-L-Ala] and cyclo[L-Tle-L-Lys-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle-D-Ala] have a potent antimicrobial activity against Staphylococcus aureus  when combined but almost no effect as a single peptide. In this study the antimicrobial activity of the peptides cyclo L-Lys(R)-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle and cyclo D-Lys(R)-D-Tle-L-Ala-D-Tle-L-Ala-D-Tle-L-Ala-D-Tle where R is –L-Arg-L-Arg-L-Arg-CO-(CH2)6-CH3  was investigated  against Staphylococcus aureus  in a broth microdilution assay.  At a concentration of 10 mM neither peptide showed any antimicrobial activity. However, when both peptides were present in the experiment a potent inhibition with a MIC value of 8.9 mM was observed. These results show that this class of peptides can be modified by branching of the side-chain of an amino acid residue in the cyclic peptide while retaining or possibly enhancing the antimicrobial activity. This observation will facilitate the optimization of antimicrobial activity and specificity of peptides with similar design.   

National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-72967OAI: oai:DiVA.org:su-72967DiVA: diva2:504650
Available from: 2012-02-21 Created: 2012-02-17 Last updated: 2015-03-16Bibliographically approved
In thesis
1. Development of antimicrobial peptides: Methodological aspects, design, synthesis and evaluation of a new class of antimicrobial peptides
Open this publication in new window or tab >>Development of antimicrobial peptides: Methodological aspects, design, synthesis and evaluation of a new class of antimicrobial peptides
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A new protective group for the indole nitrogen of the amino acid tryptophan, the Boc-sarcosinoyl-sarcosinolyl (Boc-Sar-Sar) is described. This protective group shows good stability to the reaction conditions used in solid phase peptide synthesis and can be incorporated into the peptide as Fmoc-Trp(Boc-Sar-Sar)-OH. When the peptide is cleaved from the resin with trifluororoactetic acid, the Boc group is simultaneously cleaved and the N-terminal nitrogen in the Sar-Sar group is exposed. At low pH this amino group is protonated and thereby the peptide will have higher solubility in aqueous solution. High solubility of the peptide is an important factor for the purification of peptides with reversed phase HPLC. During HPLC purification, the protonated Sar-Sar group will remain on the peptide. When the purified peptide is exposed to physiological pH, the Sar-Sar group will be cleaved and the peptide will be obtained in its fully deprotected form.

Gramicidin A (GA) is an extremely hydrophobic peptide with four tryptophan residues. To improve the solubility of GA, Fmoc-Trp(Boc-Sar-Sar)-OH was used in the solid phase synthesis of GA resulting in (H-Sar-Sar)4-GA. When this peptide was exposed to physiological pH native GA was formed.

A new class of antimicrobial peptides, represented by the enantiomers; cyclo[D-Tle-D-Lys-D-Tle-L-Ala-D-Tle-L-Ala-D-Tle-L-Ala] and cyclo[L-Tle-L-Lys-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle-D-Ala] is described. Neither of the two peptides shows any significant antimicrobial activity against Bacillus megaterium. However, when both peptides are present during the experiment a potent antimicrobial activity with an IC50 value of 2 µM could be observed. The peptides also show low hemolytic activity with an HC50 value of 316 µM. The synergistic mode of action of these peptides is dependent on the presence of both enantiomers. Circumstantial evidences indicate that the antimicrobial effect is the result of formation of peptide nanotubes within the bacterial membrane.

It is also shown that the cyclic peptides described above can be modified at the lysine residue with three arginine residues in which the N-terminus is acylated with a short fatty acid. Togheter these peptides show a synergistic mode of action against Staphylococcus aureus resulting in a MIC value of 9 µM.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2012. 75 p.
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-73366 (URN)978-91-7447-459-6 (ISBN)
Public defence
2012-03-30, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 4: Manuscript.

Available from: 2012-03-08 Created: 2012-02-21 Last updated: 2015-03-06Bibliographically approved

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