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

Authors

Eman H. M. Mohammed, Chapman UniversityFollow
Sandeep Lohan, Chapman UniversityFollow
Tarra Ghaffari, Chapman University
Shilpi Gupta, Chapman University
Rakesh K. Tiwari, Chapman UniversityFollow
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

11-28-2022

Abstract

We designed a library of 24 cyclic peptides containing arginine (R) and tryptophan (W) residues in a sequential manner [RnWn] (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 (t1/2 = 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.

Comments

This article was originally published in Journal of Medicinal Chemistry, volume 65, issue 23, in 2022. https://doi.org/10.1021/acs.jmedchem.2c01469

Recommended Citation

Mohammed, E. H. M., Lohan, S., Ghaffari, T., Gupta, S., Tiwari, R. K., Parang, K. Membrane-active cyclic amphiphilic peptides: Broad-spectrum antibacterial activity alone and in combination with antibiotics. J. Med. Chem. 2022, 65, 23, 15819–15839. https://doi.org/10.1021/acs.jmedchem.2c01469

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This work is licensed under a Creative Commons Attribution 4.0 License.