Amphiphilic Cyclic Peptide [W₄KR₅]-Antibiotics Combinations as Broad-Spectrum Antimicrobial Agents

Authors

Eman H. M. Mohammed, Chapman UniversityFollow
Sandeep Lohan, Chapman UniversityFollow
Rakesh K. Tiwari, Chapman UniversityFollow
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

3-17-2022

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.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in European Journal of Medicinal Chemistry, volume 235, in 2022. https://doi.org/10.1016/j.ejmech.2022.114278

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Recommended Citation

Mohammed EHM, Lohan S, Tiwari RK, Parang K. Amphiphilic cyclic peptide [W4KR5]-Antibiotics combinations as broad-spectrum antimicrobial agents. Eur J Med Chem. 2022;235:114278. https://doi.org/10.1016/j.ejmech.2022.114278

Copyright

Elsevier

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.