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Rigshospitalet - en del af Københavns Universitetshospital
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Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  1. One-Step Synthesis of N-Succinimidyl-4-[18F]Fluorobenzoate ([18F]SFB)

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Febrile infections in young children do not frequently induce translocation ETV6-RUNX1

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Increased risk of ALL among premature infants is not explained by increased prevalence of pre-leukemic cell clones

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Novel Cyclic Lipopeptide Antibiotics: Effects of Acyl Chain Length and Position

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Abdullah Lone
  • Thomas T Thomsen
  • Josefine Eilsø Nielsen
  • Peter W Thulstrup
  • Rasmus N Klitgaard
  • Anders Løbner-Olesen
  • Reidar Lund
  • Håvard Jenssen
  • Paul R Hansen
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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 µg/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 1-8 showed that they likely fold into α-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 (~50-60%) inserts into the bilayer compared to D2D (~30-50%). 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.

OriginalsprogEngelsk
TidsskriftBlood Cells, Molecules, and Diseases
Vol/bind24
Udgave nummer24
Sider (fra-til)4571
ISSN1079-9796
DOI
StatusUdgivet - 13 dec. 2019

ID: 59370886