Effects of N‐terminal modifications on the stability of antimicrobial peptide SAMP‐A4 analogues against protease degradation

Abstract

Infections with multidrug‐resistant (MDR) pathogens are increasingly concerning for public health. Synthesized antimicrobial peptide A4 (SAMP‐A4), a peptide computationally designed by our research team, is a potential drug candidate. However, the antimicrobial peptide SAMP‐A4 is easily degraded in serum. To obtain SAMP‐A4 analogues with high biostability, chemical modifications at its N‐terminus, including fatty acid conjugation, glycosylation and PEGylation, were carried out. The results showed that the introduction of hydrophobic fatty acids at the N‐terminus of SAMP‐A4 is better than hydrophilic glycosylation and PEGylation. With increasing fatty acid chain length, the stability of SAMP‐A4 analogues in serum and trypsin solutions is significantly improved, and the activities against MDR bacteria and Candida are significantly enhanced. There is no obvious change in haemolysis even when hexanoic acid is coupled with SAMP‐A4, so the resulting analogue SAMP‐A4‐C6, SAMP‐A4 conjugated with hexanoic acid, is the most likely of the analogues to become a drug.

Antibacterial-Based Hydrogel Coatings and Their Application in the Biomedical Field—A Review

“…The hydrophobic groups of bactericides may also damage the lipid composition of the bacterial membranes. Some widely used bactericides are antimicrobial peptides (AMPs) and quaternary ammonium compounds (QACs) [94,95].…”

Synergistic effect and antibiofilm activity of the antimicrobial peptide K11 with conventional antibiotics against multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae

“…Then, a series of 2-fold dilutions of K11 were prepared in CAMHB, 50 µL of each peptide solution was transferred to the well of a 96-well microplate. An equal volume of K. pneumoniae ATCC 70063 or K. pneumoniae ATCC BAA-1706 (10 6 CFU/mL) suspension was added, and the mixture was incubated at 37°C for 20-24 h ( Li et al., 2021 ). To examine the pH stability, the pH was adjusted to range from 2.0 to 10.0 with the following 100 mM buffers: glycine-HCl buffer (pH 2.0), sodium acetate buffer (pH 4.0), sodium phosphate buffer (pH 6.0), Tris-HCl buffer (pH 8.0), and glycine-NaOH buffer (pH 10.0).…”

Activities of a broad‐spectrum antimicrobial peptide analogue SAMP‐A4‐C8 and its combat against pneumonia in Staphylococcus aureus‐infected mice

“…9 The lipopeptide SAMP-A4-C8 (n-octanoic-VRLLRRRI) (Figure 1), a SAMP-A4 analogue that conjugated with n-octanoic acid, was found to possess higher antimicrobial activity than that of SAMP-A4. 10 We speculate that it may kill pathogens by some lethal mechanism of action. In the present research, we conducted research on its antimicrobial activity, mechanism of action and therapeutic potential against pneumonia in S. aureus-infected mice.…”

“…The lipopeptide SAMP‐A4‐C8 ( n ‐octanoic‐VRLLRRRI) (Figure 1), a SAMP‐A4 analogue that conjugated with n‐octanoic acid, was found to possess higher antimicrobial activity than that of SAMP‐A4 10 . We speculate that it may kill pathogens by some lethal mechanism of action.…”