New Antimicrobial Peptides with Repeating Unit against Multidrug-Resistant Bacteria

Abstract

With the aim of tackling the increasingly serious antimicrobial resistance and improving the clinical potential of AMPs, a facile de novo strategy was adopted in this study, and a series of new peptides comprising repeating unit (WRX) n (X represents I, L, F, W, and K; n = 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) 4 and (WRK) 5 , with n = 4 and n = 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) 4 and (WRK) 5 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) 4 exerted impressive therapeutic effects in vivo similarly to polymyxin B but displayed much lower toxicity in vivo than polymyxin B. Taken together, the newly designed peptides (WRK) 4 and (WRK) 5 presented tremendous potential as novel antimicrobial candidates in response to the growing antimicrobial resistance.

Fabrication of Supramolecular Antibacterial Nanofibers with Membrane-Disruptive Mechanism

“…Studies have shown that sodium ions, calcium ions, and other divalent ions can disturb the electrostatic interaction between AMPs and bacterial membranes through electrostatic shielding, resulting in a reduction in bacteriostatic effects. 47 In addition, divalent ions, such as calcium ions, can also competitively bind to LPS on the outer membrane of Gram-negative bacteria to reduce the antibacterial activity of AMPs. 42 This notion explains why the antibacterial effect of AMPs will decrease in the environment of ions, such as Na + , Ca 2+ , Mg 2+ , and so forth.…”

“…Next, we tested the changes in the antibacterial ability of synthetic peptides at different physiological salt concentrations. Studies have shown that sodium ions, calcium ions, and other divalent ions can disturb the electrostatic interaction between AMPs and bacterial membranes through electrostatic shielding, resulting in a reduction in bacteriostatic effects . In addition, divalent ions, such as calcium ions, can also competitively bind to LPS on the outer membrane of Gram-negative bacteria to reduce the antibacterial activity of AMPs .…”

Antimicrobial peptides–antibiotics combination: An effective strategy targeting drug‐resistant Gram‐negative bacteria

“…In the previous study, [ 30 ] K 4 and K 5 showed high antibacterial activity and low toxicity, with ideal antibacterial potential. Thus, we chose K 4 or K 5 as an adjuvant in this study, to further explore their potential in eliminating or reversing the resistance of Gram‐negative bacteria when combining them with the traditional antibiotics.…”

“…For some strains, K 5 showed better antimicrobial activity than K 4 , which may be due to its stronger α‐helix tendency, which was consistent with the previous research of our group. [ 30 ] Among all the strains tested, the antimicrobial activity of four traditional antibiotics was ranked as ciprofloxacin, rifampicin, gentamicin, and imipenem. And the vast majority showed lower antimicrobial activity against the obtained antibiotics‐resistant bacteria than the standard strains.…”

“…Our group found that, [ 30 ] two novel peptides K 4 (WRKWRKWRKWRK‐NH 2 ) and K 5 (WRKWRKWRKWRKWRK‐NH 2 ) showed excellent antibacterial activity through various mechanisms, low toxicity, and low drug resistance in contrast to the traditional antibiotics. Although the size and total charge of K 4 and K 5 were different, it was found in the previous study that the MICs difference between them against the standard strains or clinical drug‐resistant strains was only within two folds.…”