Antimicrobial activity and stability of the d-amino acid substituted derivatives of antimicrobial peptide polybia-MPI

Abstract

Antimicrobial peptide has the potential to be developed as new kind of antimicrobial agents with novel action mechanism. However, the susceptibility to protease is a drawback for potential peptides to be clinical used. d-amino acid substitution can be one way to increase the proteolytic stability of peptides. In the present study, we synthesized the d-lysines substituted analog (d-lys-MPI) and the d-enantiomer of polybia-MPI (D-MPI) to improve the proteolytic resistance of polybia-MPI. Our results showed that, the stability of its d-amino acid partially substituted analog d-lys-MPI was increased. However, it lost antimicrobial activity at the tested concentration with the loss of α-helix content. As shown in the CD spectra, after substitution, the spectra of D-MPI is symmetrical to MPI, indicated it turned into left hand α-helical conformation. Excitingly, the stability of D-MPI toward the tested protease was improved greatly. Notably, the antimicrobial activity of D-MPI was comparable to its L-counterpart MPI, even improved. In addition, the hemolytic activity of D-MPI was lowered. This also indicated that the action target of antimicrobial peptide polybia-MPI was not chiral specific. So, D-MPI may offer a therapeutic strategy to defend the infection of microbes, considering its stability to protease and relatively lower cytotoxicity to human erythrocytes.

Purification of Bioactive Peptide with Antimicrobial Properties Produced by Saccharomyces cerevisiae

“…Similar reports have shown that antibacterial peptides isolated from different microbial sources are able to persist at high temperatures without any change in the antimicrobial activity [23,24].…”

Antifungal activity of a de novo synthetic peptide and derivatives against fungal food contaminants

“…This indicates that KK14 and its d ‐enantiomer do not use a specific receptor to inhibit fungal growth but rather use, at least partially, a membrane‐permeabilising mechanism. Although d ‐enantiomerization of a single residue can reduce haemolytic activity, full enantiomerization is usually more advised to avoid the loss of activity and structural deficiencies of the peptide as shown with polybia‐MPI . Interestingly, l and d ‐enantiomers of thanatin display the same antifungal activity, although the d ‐enantiomer is much less active against Gram‐negative bacteria …”

Computer-Aided Design of Antimicrobial Peptides: Are We Generating Effective Drug Candidates?

“…Finally, AMPs are known to have diverse modes of action depending on the bacterial targets they interact with and, therefore, are promising candidates for multi-target antibacterial treatments. Although these characteristics appear as promising features for drug development, some disadvantages have been pinpointed for AMP-based therapies, including chemical and physical instability (Zhao et al, 2016), proteolytic degradation (Pachon-Ibanez et al, 2017), short half-life and rapid elimination (Lombardi et al, 2015), slow tissue penetration (Koczulla et al, 2003), toxicity toward healthy human cells, and cell specificity (Oshiro et al, 2019). Based on that, an increasing number of computational strategies are underway, aiming at overcoming these obstacles by optimizing AMP sequences.…”