TY - JOUR
T1 - Stapling of Peptides Potentiates
T2 - The Antibiotic Treatment of Acinetobacter baumannii In Vivo
AU - Schouten, Gina K.
AU - Paulussen, Felix M.
AU - Kuipers, Oscar P.
AU - Bitter, Wilbert
AU - Grossmann, Tom N.
AU - van Ulsen, Peter
N1 - Funding Information: Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant, agreement no. 713669. Furthermore, this project, with the project number 16433, is part of the research program NACTAR, which is partly financed by the Dutch Research Counsel (NOW). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2
Y1 - 2022/2
N2 - The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.
AB - The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.
KW - Stapled antimicrobial peptides
KW - Synergy
KW - Zebrafish larvae infection model
UR - http://www.scopus.com/inward/record.url?scp=85125066326&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125066326&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/antibiotics11020273
DO - https://doi.org/10.3390/antibiotics11020273
M3 - Article
SN - 2079-6382
VL - 11
SP - 1
EP - 16
JO - Antibiotics
JF - Antibiotics
IS - 2
M1 - 273
ER -