Insights into Mechanistic and Synergistic Aspects of Novel Synthetic Short Cationic Antibacterial Peptides

Two series of short cationic antimicrobial peptides (CAMPs) in which modification of the imidazole ring of histidine by bulkier alkyl substituents was done using regiospecific and radical-mediated alkylation. The synthesized CAMPs were evaluated for their antibacterial efficacy using different bacterial strains. In particular, CAMP 11i was found to be most active against L. monocytogenes and other CAMPs such as 10e and 11g exhibited moderate activity against S. aureus. The most active compounds were tested against Hek-293 and HeLa cells with active CAMPs 11i and 11g with calculation of selectivity index against the L. monocytogenes and S. aureus, respectively as compared to mammalian cells. The SEM studies were also performed which confirmed the disruption of cell wall of treated bacteria using CAMP 11i at its MIC concentration. The selectivity of active peptides towards bacterial cells in comparison to mammalian cells was checked using tryptophan quenching studies on small unilamellar vesicles. The results were found to be perfectly in corroboration with the differences between bacterial and mammalian cell membrane composition, thereby, indicating that these peptides kill the bacterial cells via conjugation with the cell membrane. Synergy studies of CAMPs in combination with known clinical antibacterial drugs against L. monocytogenes further displayed enhanced antibacterial efficacy.