Structure-Activity Study of an All-D Antimicrobial Octapeptide D2D
| Autor: | Paul R. Hansen, Rasmus N. Klitgaard, Håvard Jenssen, Reidar Lund, Peter W. Thulstrup, Thomas T. Thomsen, Abdullah Lone, Josefine Eilsø Nielsen, Anders Løbner-Olesen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Acinetobacter baumannii
Circular dichroism Antibiotics Pharmaceutical Science Peptide Small angle X-ray scattering 01 natural sciences Analytical Chemistry chemistry.chemical_compound antimicrobial peptides Anti-Infective Agents X-Ray Diffraction time-kill kinetics Drug Discovery Protein secondary structure Alanine chemistry.chemical_classification 0303 health sciences Molecular Structure Minimum inhibitory concentration Chemistry Antimicrobial Chemistry (miscellaneous) Pseudomonas aeruginosa Molecular Medicine Antimicrobial peptides Hydrophobic and Hydrophilic Interactions Oligopeptides Lead compound Time-kill kinetics Staphylococcus aureus Stereochemistry medicine.drug_class small angle X-ray scattering Microbial Sensitivity Tests minimum inhibitory concentration Article Structure-Activity Relationship 03 medical and health sciences Escherichia coli medicine Physical and Theoretical Chemistry hemolytic activity 030304 developmental biology Bacteria Dose-Response Relationship Drug 010405 organic chemistry D-peptides Organic Chemistry Hemolytic activity d-peptides 0104 chemical sciences circular dichroism |
| Zdroj: | Lone, A, Thomsen, T T, Nielsen, J E, Thulstrup, P W, Klitgaard, R N, Løbner-Olesen, A, Lund, R, Jenssen, H & Hansen, P R 2019, ' Structure-Activity Study of an All-D Antimicrobial Octapeptide D2D ', Molecules, vol. 24, no. 24, 4571 . https://doi.org/10.3390/molecules24244571 Molecules Volume 24 Issue 24 'Molecules ', vol: 24, pages: 4571-1-4571-17 (2019) |
| ISSN: | 1420-3049 |
| Popis: | The increasing emergence of multi-drug resistant bacteria is a serious threat to public health worldwide. Antimicrobial peptides have attracted attention as potential antibiotics since they are present in all multicellular organisms and act as a first line of defence against invading pathogens. We have previously identified a small all-d antimicrobial octapeptide amide kk(1-nal)fk(1-nal)k(nle)-NH2 (D2D) with promising antimicrobial activity. In this work, we have performed a structure-activity relationship study of D2D based on 36 analogues aimed at discovering which elements are important for antimicrobial activity and toxicity. These modifications include an alanine scan, probing variation of hydrophobicity at lys5 and lys7, manipulation of amphipathicity, N-and C-termini deletions and lys-arg substitutions. We found that the hydrophobic residues in position 3 (1-nal), 4 (phe), 6 (1-nal) and 8 (nle) are important for antimicrobial activity and to a lesser extent cationic lysine residues in position 1, 2, 5 and 7. Our best analogue 5, showed MICs of 4 µ g/mL against A. baumannii, E. coli, P. aeruginosa and S. aureus with a hemolytic activity of 47% against red blood cells. Furthermore, compound 5 kills bacteria in a concentration-dependent manner as shown by time-kill kinetics. Circular dichroism (CD) spectra of D2D and compounds 1&ndash 8 showed that they likely fold into &alpha helical secondary structure. Small angle x-ray scattering (SAXS) experiments showed that a random unstructured polymer-like chains model could explain D2D and compounds 1, 3, 4, 6 and 8. Solution structure of compound 5 can be described with a nanotube structure model, compound 7 can be described with a filament-like structure model, while compound 2 can be described with both models. Lipid interaction probed by small angle X-ray scattering (SAXS) showed that a higher amount of compound 5 (~50&ndash 60%) inserts into the bilayer compared to D2D (~30&ndash 50%). D2D still remains the lead compound, however compound 5 is an interesting antimicrobial peptide for further investigations due to its nanotube structure and minor improvement to antimicrobial activity compared to D2D. |
| Databáze: | OpenAIRE |
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