Antibacterial activity of 2-(4-aminopiperidin-4-yl)acetic acid (β3,3-Pip) derivatives and its peptides conjugated with lauric acid through the side chain against methicillin-resistant Staphylococcus aureus (MRSA).

The present work describes the synthesis, characterization, and antibacterial efficacy of cationic β-amino acid derivatives and peptides, H2N-β3,3-Pip(LA)-PEA, P1; and H2N-β3,3-Pip (ULA)-PEA, P2; H2N-β3,3-Pip(LA)-β2,2-Ac6c-PEA, P3; and H2N- β3,3-Pip(ULA)- β2,2-Ac6c-PEA, P4. The compounds P1-P4 were evaluated against the WHO priority multidrug-resistant (MDR) ESKAPE panel pathogens. P2 and P4 exhibited potent activity with MIC values ranging from 3.1 μM to 6.2 μM against MDR pathogens. Further, the kill-kinetics assay demonstrated that P2 and P4 eliminate MRSA in a concentration and time-dependent manner. P2 and P4 also showed the MRSA biofilm prevention and disruption of preformed biofilm. The SEM images and PI permeability assays confirmed the bacterial killing by P2 and P4 through membrane disruption, highlighting their strong bactericidal activity. Additionally, the very low hemolytic and cytotoxic activity of peptides indicate these compounds as promising candidates for further investigation. Subsequently, the compounds P2 and P4 showed synergistic effects with vancomycin. Altogether, the present study highlights the potential of short cationic β-amino acid derivatives and peptides conjugated with lauric acid through the side chain as novel antibacterial agents for combating antimicrobial resistance (AMR).