Amphiphilic cyclic peptide [W4KR5]-Antibiotics combinations as broad-spectrum antimicrobial agents

Abstract

Linear and cyclic amphiphilic peptides, (W₄KR₅) and [W₄KR₅], were evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including four multi-drug resistant strains and the corresponding four non-resistant strains. Cyclic peptide [W₄KR₅] showed higher antibacterial activity than the linear (W₄KR₅) counterpart. Cyclic [W₄KR₅] was subjected to combination (physical mixture or covalent conjugation) with meropenem as a model antibiotic to study the impact of the combination on antimicrobial activity. A physical mixture of meropenem and [W₄KR₅] showed synergistic antibacterial activity against Gram-negative P. aeruginosa (ATCC BAA-1744) and P. aeruginosa (ATCC 27883) strains. [W₄KR₅] was further subjected to extensive antibacterial studies against additional 10 bacteria strains, showing significant antibacterial efficacy against Gram-positive bacteria strains. Combinations studies of [W₄KR₅] with an additional 9 commercially available antibiotics showed significant enhancement in antibacterial activity for all tested combinations, especially with tetracycline, tobramycin, levofloxacin, clindamycin, daptomycin, polymyxin, kanamycin, and vancomycin. Time-kill kinetics assay and flow cytometry results exhibited that [W₄KR₅] had a time-dependent synergistic effect and membrane disruption property. These data indicate that [W₄KR₅] improves the antibacterial activity, presumably by facilitating the internalization of antibiotics and their interaction with the intracellular targets. This study introduces a potential strategy for treating multidrug-resistant pathogens by combining [W₄KR₅] and a variety of classical antibiotics to improve the antibacterial effectiveness.