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.
Antimicrobial peptides and their analogues have become substitutes for antibiotics in recent years. The antimicrobial peptide analogue SAMP‐A4‐C8 (n‐octanoic‐VRLLRRRI) with high antimicrobial activity was found in our lab. We speculate that it may kill pathogens by some lethal mechanism of action. In the present investigation, the microbicidal activities of SAMP‐A4‐C8 and its mechanism of action were investigated. The results demonstrated that SAMP‐A4‐C8 had lethal activities against Staphylococcus aureus and Candida albicans by cell disruption. Based on its microbicidal activities, we believe that it is worth further research for its potential as drug candidate. The results showed that SAMP‐A4‐C8, with low propensity to induce the resistance of S. aureus and C. albicans, could kill the persister cells of S. aureus and C. albicans, exhibited biofilm forming inhibition activity and preformed biofilm eradication ability against S. aureus and C. albicans, and displayed therapeutic potential on pneumonia in S. aureus‐infected mice by reducing lung inflammation. The present study provided a promising drug candidate in the war against multidrug resistance.
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