Stapled beta;-Hairpin Antimicrobial Peptides with Improved Stability and Activity against Drug-Resistant Gram-Negative Bacteria

摘要

Different stapling techniques have been used recentlyto addressthe subpar performance of antimicrobial peptides (AMPs) in clinicaltrials with ample focus on alpha;-helical AMPs. In comparison, asystematic evaluation of such strategies on beta;-hairpin AMPs islacking. Herein, we report the design, synthesis, and evaluation ofa library of all-hydrocarbon-stapled beta;-hairpin AMPs with variationin key parameters intended as potent therapeutics against drug-resistantpathogens. We observed an interesting interplay between the activity,stability, and structural strength. Single-stapled peptides with a6-carbon staple at peptide termini such as 5(c(6)) displayedthe most potent activity against colistin-resistant clinical isolates.Using imaging techniques, we observed translocation of 5(c(6)) across bacterial membranes without causing extensive damage. Overall,we have engineered novel all-hydrocarbon-stapled beta;-hairpin AMPswith structural and functional proficiency that can effectively combatresistant pathogens, with findings from this study a point of referencefor future interests in developing novel beta;-hairpin AMPs.