Synthesis, Characterization, and Antimicrobial Activity of Ultra-Short Cationic β-Peptides

The development of new antibiotics is urgently required because of the rapidly growing resistance against conventional antibiotics. The antimicrobial peptides show potential as small antibiotic molecules. The stability of peptides is a primary concern for the use of peptides as drugs. Introducing β-amino acids into peptide sequences can be useful in preventing biological degradation by proteolytic enzymes. Herein, we describe the synthesis, characterization, and antimicrobial activity of ultra-short cationic β-peptides, LA-β^3,3-Pip-β^2,2-Ac₆c-PEA, P1; LA-β^3,3-Pip(G)-β^2,2-Ac₆c-PEA, P2; LA^U-β^3,3-Pip-β^2,2-Ac₆c-PEA, P3, and LA^U-β^3,3-Pip(G)-β^2,2-Ac₆c-PEA, P4. Peptides P1-P4 were evaluated against Gram-negative, Gram-positive, MRSA, and multi-drug resistant E. coli (MDR-E. coli). P3 exhibited the most potent antimicrobial activity against E. coli, S. epidermidis, S. aureus, K. pneumoniae, S. mutans, and E. faecalis, with MIC values 0.5, 2, 0.5, 1, 2, and 1 μg/mL, respectively. P3 exhibited time- and concentration-dependent bactericidal activities against E. coli, S. aureus, and E. faecalis with a killing rate of 1.6 logs/h. The treatment of E. coli with peptide P3 showed membrane disruption. In addition, P3 exhibited the inhibition of biofilm produced by E. coli, synergism with antibiotics (ciprofloxacin, streptomycin, and ampicillin), 100% cell viability against AML12, RAW 264.7, and HEK-293 cell lines at 1, and 10 μg/mL concentrations.