Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

Abstract

We designed a library of 24 cyclic peptides containing arginine (R) and tryptophan (W) residues in a sequential manner [R n W n ] (n = 2–7) to study the impact of the hydrophilic/hydrophobic ratio, charge, and ring size on the antibacterial activity against Gram-positive and Gram-negative strains. Among peptides, 5a and 6a demonstrated the highest antimicrobial activity. In combination with 11 commercially available antibiotics, 5a and 6a showed remarkable synergism against a large panel of resistant pathogens. Hemolysis (HC50 = 340 μg/mL) and cell viability against mammalian cells demonstrated the selective lethal action of 5a against bacteria over mammalian cells. Calcein dye leakage and scanning electron microscopy studies revealed the membranolytic effect of 5a. Moreover, the stability in human plasma (t 1/2 = 3 h) and the negligible ability of pathogens to develop resistance further reflect the potential of 5a for further development as a peptide-based antibiotic.

Application of tobramycin benzyl ether as an antibiotic adjuvant capable of sensitizing multidrug-resistant Gram-negative bacteria to rifampicin

“…17 To verify whether LPS interactions are also crucial for the observed synergy between compound 1 and rifampicin, the checkerboard assays were repeated in the presence of higher Mg 2+ and monovalent Na + concentrations. 46,47…”

“…the observed synergy between compound 1 and rifampicin, the checkerboard assays were repeated in the presence of higher Mg 2+ and monovalent Na + concentrations. 46,47 The synergistic interaction of rifampicin in combination with compound 1 against the reference strains was primarily lost upon the addition of 20 mM Mg 2+ , with a reduction in the potentiation by 8-to 512-fold (Fig. 6).…”

“…The broth microdilution and checkerboard assays in the presence of higher Mg 2+ and Na + concentrations were conducted as previously described. 46,47 The tests were carried out as described in the aforementioned assays wherein the growth media was supplemented with either MgCl 2 or NaCl and to achieve a concentration of 20 and 150 mM, respectively.…”

Double-Network Hydrogel with Strengthened Mechanical Property for Controllable Release of Antibacterial Peptide

“…Typically, amphiphilic AMPs facilitate the formation of transmembrane ion channels on the bacterial cell membranes, disrupting the integrity of the membrane, inducing cytoplasmic leakage, and leading to cell death . Such a unique and physical action is less likely to promote bacterial resistance. − Furthermore, the amphiphilic nature of AMPs normally enables them to self-assemble and form hydrogel, making them suitable candidates as antibacterial biomaterials and 3D cell culture scaffolds . However, there are some shortcomings for AMP hydrogels that have limited their applications in the biomaterial fields.…”

Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance

“…AMPs typically span several secondary structures including α-helix, β-sheet, random coil, extended conformation, and loop. , Once exposed to the bacterial surface, the cationic residues of amphiphilic AMPs interact with lipopolysaccharide (LPS) or lipoteichoic acid (LTA), which are negatively charged components of bacterial membrane surfaces. Moreover, the hydrophobic part of AMP would be inserted into the phospholipid bilayer, leading to membrane damage, depolarization or lysis, and even cell death. ,− Among the hydrophobic amino acids of AMPs, tryptophan (Trp) and phenylalanine (Phe) with aromatic ring side chains, have been proven to be crucial for their specific affinity to the phospholipid layers and the penetration into the bacteria membrane. − Although AMPs have great potential to replace antibiotics for the treatment of infections caused by MDR bacteria, several drawbacks of AMPs such as easy degradation, systemic toxicity, high manufacturing cost, and insufficient antimicrobial activity have not been satisfactorily addressed. , …”