PepBiotics, novel cathelicidin-inspired antimicrobials to fight pulmonary bacterial infections

Martin van Eijk, Albert van Dijk, Cornelis K. van der Ent, Hubertus G.M. Arets, Eefjan Breukink, Nico van Os, Roy Adrichem, Sven van der Water, Rita Lino Gómez, Maartje Kristensen, Martin Hessing, Shehrazade Jekhmane, Markus Weingarth, Ruud A.W. Veldhuizen, Edwin J.A. Veldhuizen*, Henk P. Haagsman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Antimicrobial peptides are considered potential alternatives to antibiotics. Here we describe the antibacterial properties of a family of novel cathelicidin-related (CR-) peptides, which we named PepBiotics, against bacteria typically present in cystic fibrosis (CF) patients. Methods: Broth dilution assays were used to determine antibacterial activity of PepBiotics under physiological conditions, as well as development of bacterial resistance against these peptides. Toxicity was tested in mice and cell cultures while molecular interactions of PepBiotics with bacterial membrane components was determined using CD, ITC and LPS/LTA induced macrophage studies. Results: A relatively small number of PepBiotics remained highly antibacterial against CF-related respiratory pathogens Pseudomonas aeruginosa and Staphylococcus aureus, at high ionic strength and low pH. Interestingly, these PepBiotics also prevented LPS/LTA induced activation of macrophages and was shown to be non-toxic to primary human nasal epithelial cells. Furthermore, both P. aeruginosa and S. aureus were unable to induce resistance against CR-163 and CR-172, two PepBiotics selected for their excellent antimicrobial and immunomodulatory properties. Toxicity studies in mice indicated that intratracheal administration of CR-163 was well tolerated in vivo. Finally, interaction of CR-163 with bacterial-type anionic membranes but not with mammalian-type (zwitterionic lipid) membranes was confirmed using ITC and 31P solid state NMR. Conclusions: PepBiotics are a promising novel class of highly active antimicrobial peptides, of which CR-163 showed the most potential for treatment of clinically relevant (CF-) pathogens in physiological conditions. General significance: These observations emphasize the therapeutic potential of PepBiotics against CF-related bacterial respiratory infections.

Original languageEnglish
Article number129951
Pages (from-to)1-11
JournalBiochimica et Biophysica Acta - General Subjects
Volume1865
Issue number9
DOIs
Publication statusPublished - Sept 2021

Keywords

  • Antibiotics
  • Antimicrobial peptide
  • Antimicrobial resistance
  • Bacterial infections
  • Cystic Fibrosis
  • Lung
  • Membrane peptide therapeutic
  • Pulmonary infection

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