Short hybrid peptides incorporating β- and γ-amino acids as antimicrobial agents

[Display omitted] •The hybrid peptides containing β- and γ-amino acids were synthesized, characterized and evaluated as antimicrobial agents.•αγ hybrid peptide, LA-Lys(Z)-Gpn-PEA, P4 was found more active against P. aeruginosa and S. aureus.•Peptide P4 exhibited lowest haemolytic activity and negligible cytotoxicity against human cancer cell lines A549, PC-3 and HCT-116 at its MIC concentration. The peptides containing β- and γ-amino acids, LA-Lys(Z)-PEA, P1; LA-Lys(Z)-β3,3-Ac6c-PEA, P2; LA-Orn(Z)-β3,3-Ac6c-PEA, P3; LA-Lys(Z)-Gpn-PEA, P4; LA-Orn(Z)-Gpn-PEA, P5; LA-Lys(Z)-γ4-Phe-PEA, P6, LA-γ4-Leu-Lys(Z)-PEA, P7 and LA-β3,3-Pip(Ac)-Lys(Z)-PEA, P8 were synthesized, characterized and evaluated against Gram-positive and Gram-negative bacteria. Among all, peptides P2, P3, P4 and P5 exhibited potent activity (MIC 6.25μM) against S. aureus MTCC 737 and P. aeruginosa MTCC 424. In order to understand the efficacy of peptides and mechanism of action, time kill kinetics and fluorescence microscopic studies were performed against S. aureus and P. aeruginosa for the peptides P2, P3, P4 and P5. P4 took half time to show the bactericidal effect on P. aeruginosa and S. aureus in comparison to P2 at their 2x MICs. Fluorescence microscopic studies suggested that peptides P2 and P4 both killed the bacteria via membrane disruption. Further, P4 exhibited lowest haemolytic activity among active peptides and negligible cytotoxic activity against human cancer cell lines A-549, PC-3 and HCT-116 at its MIC.