Abstract:
Membrane active peptides have found great interest as drug candidates due to their unique mode of action and availability in nature. In the past 20 years, beta lactamase-mediated antibiotic resistance has become a lethal issue with the widespread of antibiotic cleaving beta-lactamase enzyme due to the misuse of beta-lactam type antibiotics. In this context, antimicrobial peptides are promising broad-spectrum al ternatives to conventional antibiotics in the era of evolving bacterial resistance. In an effort to propose peptide drugs against antibiotic resistance, the understanding of how peptide drugs take action is essential. Here, the goal was to propose novel peptide an timicrobials that can efficiently inhibit periplasmic beta-lactamase and internalize into bacteria. For this aim, the cell-penetrating peptide pVEC and its first five residues (LLIIL) deleted variant del5 pVEC, were analyzed using molecular dynamics simula tions to gain insights about the mechanism and free energy of the lipid bilayer translo cation, and the contribution of the LLIIL residues to this peptide’s uptake. Motivated by the pVEC sequence and the studies on pVEC emphasizing the importance of its LLIIL residues to the uptake of the peptide, the approach was to build chimeric se quences, by combining the LLIIL residues of pVEC with the beta-lactamase inhibitory peptides to facilitate their uptake. Our results show that the addition of LLIIL to the beta-lactamase inhibitory peptides increase their membrane permeabilizing potential. Interestingly, the addition of this short stretch of hydrophobic residues also modified the inhibitory peptides such that they acquired antimicrobial property. The results suggest that addition of the hydrophobic LLIIL residues to the peptide N-terminus may offer a promising strategy to design novel antimicrobial peptides in the battle against antibiotic resistance.
