Stapled ß-Hairpin Antimicrobial Peptides with Improved Stability and Activity against Drug-Resistant Gram-Negative Bacteria.
J Med Chem
; 66(13): 8498-8509, 2023 07 13.
Article
em En
| MEDLINE
| ID: mdl-37357499
ABSTRACT
Different stapling techniques have been used recently to address the subpar performance of antimicrobial peptides (AMPs) in clinical trials with ample focus on α-helical AMPs. In comparison, a systematic evaluation of such strategies on ß-hairpin AMPs is lacking. Herein, we report the design, synthesis, and evaluation of a library of all-hydrocarbon-stapled ß-hairpin AMPs with variation in key parameters intended as potent therapeutics against drug-resistant pathogens. We observed an interesting interplay between the activity, stability, and structural strength. Single-stapled peptides with a 6-carbon staple at peptide termini such as 5(c6) displayed the most potent activity against colistin-resistant clinical isolates. Using imaging techniques, we observed translocation of 5(c6) across bacterial membranes without causing extensive damage. Overall, we have engineered novel all-hydrocarbon-stapled ß-hairpin AMPs with structural and functional proficiency that can effectively combat resistant pathogens, with findings from this study a point of reference for future interests in developing novel ß-hairpin AMPs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Catiônicos Antimicrobianos
/
Peptídeos Antimicrobianos
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article