TY - JOUR
T1 - PepBiotics, novel cathelicidin-inspired antimicrobials to fight pulmonary bacterial infections
AU - van Eijk, Martin
AU - van Dijk, Albert
AU - van der Ent, Cornelis K.
AU - Arets, Hubertus G.M.
AU - Breukink, Eefjan
AU - van Os, Nico
AU - Adrichem, Roy
AU - van der Water, Sven
AU - Lino Gómez, Rita
AU - Kristensen, Maartje
AU - Hessing, Martin
AU - Jekhmane, Shehrazade
AU - Weingarth, Markus
AU - Veldhuizen, Ruud A.W.
AU - Veldhuizen, Edwin J.A.
AU - Haagsman, Henk P.
N1 - Funding Information:
The authors would like to thank Lynda McCaig for her excellent help with the animal experiments. The authors acknowledge financial support from “ Nederlandse Cystic Fibrosis Stichting ” and ZonMw (project 95104010 ).
Publisher Copyright:
© 2021 The Authors
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Antimicrobial peptide
KW - Antimicrobial resistance
KW - Bacterial infections
KW - Cystic Fibrosis
KW - Lung
KW - Membrane peptide therapeutic
KW - Pulmonary infection
UR - http://www.scopus.com/inward/record.url?scp=85108670162&partnerID=8YFLogxK
U2 - 10.1016/j.bbagen.2021.129951
DO - 10.1016/j.bbagen.2021.129951
M3 - Article
C2 - 34147544
AN - SCOPUS:85108670162
SN - 0304-4165
VL - 1865
SP - 1
EP - 11
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
IS - 9
M1 - 129951
ER -