New Antimicrobial Peptides with Repeating Unit against Multidrug-Resistant Bacteria.

With the aim of tackling the increasingly serious antimicrobial resistance and improving the clinical potential of AMPs, a facile strategy was adopted in this study, and a series of new peptides comprising repeating unit (WRX) (X represents I, L, F, W, and K; = 2, 3, 4, or 5) and amidation at C-terminus were designed. Most of the newly designed peptides exhibited a broad range of excellent antimicrobial activities against various bacteria, especially difficult-to-kill multidrug-resistant bacteria clinical isolates. Among (WRK) and (WRK), with = 4 and = 5 of repeating unit WRK, the highest selectivity for anionic bacterial membranes over a zwitterionic mammalian cell membrane is presented with strong antimicrobial potential and low toxicity. Additionally, both (WRK) and (WRK) emerged with fast killing speed and low tendency of resistance in sharp contrast to the conventional antibiotics ciprofloxacin, gentamicin, and imipenem, as well as having antimicrobial activity through multiple mechanisms including a membrane-disruptive mechanism and an intramolecular mechanism (nucleic acid leakage, DNA binding and ROS generation) characterized by a series of assays. Furthermore, (WRK) exerted impressive therapeutic effects similarly to polymyxin B but displayed much lower toxicity than polymyxin B. Taken together, the newly designed peptides (WRK) and (WRK) presented tremendous potential as novel antimicrobial candidates in response to the growing antimicrobial resistance.