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

Abstract

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 11 i was found to be most active against L. monocytogenes and other CAMPs such as 10 e and 11 g exhibited moderate activity against S. aureus.The most active compounds were tested against Hek‐293 and HeLa cells with active CAMPs 11 i and 11 g with calculation of selectivity index against the L. monocytogenesand 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 11 i 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.

Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery

“…It was suggested that this class of peptides act by selectively binding to negatively charged microbial membranes over the neutral mammalian membranes, and disrupt the cell membranes leading to lysis of the microbial cells. 144 Mittal et al 145 reported another class of modified histidine containing short cationic antimicrobial peptides (Figure 8). Peptides were screened against S. aureus, Listeria monocytogenes, E. coli, Vibrio cholerae and Enterococcus 165 showed the most significant activity against L. monocytogenes with IC 50 values of 9.3 μg/ml, but was inactive against all other strains.…”

“…Mittal et al 145 reported another class of modified histidine containing short cationic antimicrobial peptides (Figure 8). Peptides were screened against S. aureus , Listeria monocytogenes , E. coli , Vibrio cholerae and Enterococcus faecalis .…”

“…Peptide 165 showed the most significant activity against L. monocytogenes with IC 50 values of 9.3 μg/ml, but was inactive against all other strains. The mechanistic studies revealed that the selectivity of tripeptide towards bacterial cell membranes arises due to the differences between negatively charged phospholipids of bacterial and zwitterionic phospholipids and cholesterol of mammalian cell membranes 145 …”

“…The mechanistic studies revealed that the selectivity of tripeptide towards bacterial cell membranes arises due to the differences between negatively charged phospholipids of bacterial and zwitterionic phospholipids and cholesterol of mammalian cell membranes. 145 In a recent report on antimicrobial peptides, Sharma et al designed a series of C-2 arylated ring-modified histidine contaning ultrashort peptides and investigated their antimicrobial activity against various strains with detailed mechanism of action against C. neoformans (Figure 9). This systematic study lead to discovery of a lead potent compound, His 167 act through a multistep process starting with membrane permeablization, followed by cell wall disruption and interaction and lysis of genetic material leading to cell death.…”