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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 9; p. 129951
• Main Authors: van Eijk, Martin, van Dijk, Albert, van der Ent, Cornelis K., Arets, Hubertus G.M., Breukink, Eefjan, van Os, Nico, Adrichem, Roy, van der Water, Sven, Lino Gómez, Rita, Kristensen, Maartje, Hessing, Martin, Jekhmane, Shehrazade, Weingarth, Markus, Veldhuizen, Ruud A.W., Veldhuizen, Edwin J.A., Haagsman, Henk P.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2021
• Subjects: antibacterial properties; Antibiotics; Antimicrobial peptide; antimicrobial peptides; Antimicrobial resistance; Bacterial infections; Cystic Fibrosis; epithelium; humans; ionic strength; lipids; Lung; macrophages; Membrane peptide therapeutic; nose; Pseudomonas aeruginosa; Pulmonary infection; therapeutics; toxicity; zwitterions; Bacterial infections; Cystic Fibrosis; Antibiotics; Lung; Antimicrobial resistance; Membrane peptide therapeutic; Pulmonary infection; Antimicrobial peptide
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129951

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. 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. 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. 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. These observations emphasize the therapeutic potential of PepBiotics against CF-related bacterial respiratory infections. •Novel AMPs, PepBiotics, based on a unique core sequence (patent pending) are developed.•PepBiotics are active against CF- pathogens in high ionic strength and low pH (CF-) environment.•PepBiotics are non-toxic and don't induce antimicrobial resistance•PepBiotics neutralize LPS-induced inflammation in vitro