Antimicrobial activity of α/β hybrid peptides incorporating tBu-β^3,3Ac₆c against methicillin-resistant Staphylococcus aureus

The incorporation of β-amino acids into peptides is a promising approach to develop proteolytically stable therapeutic agents. Short α/β hybrid peptides containing tBu-β^3,3Ac₆cː H₂N-Lys-tBu-β^3,3Ac₆c-PEA, P1; H₂N-Orn-tBu-β^3,3Ac₆c-PEA, P2; H₂N-Arg-tBu-β^3,3Ac₆c-PEA, P3; LA-Lys-tBu-β^3,3Ac₆c-PEA, P4; LA-Orn-tBu-β^3,3Ac₆c-PEA, P5; LA-Arg-tBu-β^3,3Ac₆c-PEA, P6; LA^u-Lys-tBu-β^3,3Ac₆c-PEA, P7; LA^u-Orn-tBu-β^3,3Ac₆c-PEA, P8; and LA^u-Arg-tBu-β^3,3Ac₆c-PEA, P9 were prepared. The antimicrobial efficacies of all the peptides were evaluated against ESKAPE pathogens, along with a small panel of multi-drug resistant (MDR) clinical isolates of S. aureus. Among all the peptides, P4, P6, and P7 showed significant efficacies against P. aeruginosa, S. aureus, and MRSA with an MIC value ranging from 6.25 to 12.5 μM. Further, in vitro, anti-staphylococcal assessment with their antimicrobial synergy of the peptides P4, P6, and P7 was carried out against MRSA, due to its better efficacy. The peptides P6 and P7 exhibited MRSA biofilm inhibition of 70% and 77%, respectively, at 4×MIC concentration. At its MIC concentration, about 19% hemolysis was observed for P4, P6, and P7.