Structural Insights into and Activity Analysis of the Antimicrobial Peptide Myxinidin

Abstract

eThe marine environment has been poorly explored in terms of potential new molecules possessing antibacterial activity. Antimicrobial peptides (AMPs) offer a new potential class of pharmaceuticals; however, further optimization is needed if AMPs are to find broad use as antibiotics. We focused our studies on a peptide derived from the epidermal mucus of hagfish (Myxine glutinosa L.), which was previously characterized and showed high antimicrobial activity against human and fish pathogens. In the present work, the activities of myxinidin peptide analogues were analyzed with the aim of widening the original spectrum of action of myxinidin by suitable changes in the peptide primary structure. The analysis of key residues by alanine scanning allowed for the design of novel peptides with increased activity. We identified the amino acids that are of the utmost importance for the observed antimicrobial activities against a set of pathogens comprising both Gram-negative and Gram-positive bacteria. Overall, optimized bactericidal potency was achieved by adding a tryptophan residue at the N terminus and by the simultaneous substitution of residues present in positions 3, 4, and 11 with arginine. These results indicate that the myxinidin analogues emerge as an attractive alternative for treating drug-resistant infectious diseases and provide key insights into a rational design for novel agents against these pathogens.

Action of antimicrobial peptides and their prodrugs on model and biological membranes

“…Neither of the 2 WMR‐based peptides exhibited any dose‐dependent haemolysis within the concentration range (Figure B). In this regard, there were no significant differences observed between these AAG‐modified all‐D peptides and the unmodified parent all‐L peptide …”

“…Activity differentials up to 128 for P18, and at least of 8, for WMR, were obtained against E. coli by prodrug modification of these peptides (MICs of 256 and >128 μM, respectively). The parent sequences of the peptides investigated here have reported MICs against E. coli of 3.13 to 6.25 μM for P18 and 2 μM for WMR . It appears therefore that the addition of AAG residues at the N‐termini of the parent peptides had no marked effect on the antimicrobial activity of P18 but reduced the potency of WMR against E. coli .…”

“…In this regard, there were no significant differences observed between these AAG-modified all-D peptides and the unmodified parent all-L peptide. 31…”

Design and membrane-disruption mechanism of charge-enriched AMPs exhibiting cell selectivity, high-salt resistance, and anti-biofilm properties

“…In previous studies, myxinidin, exerted effects against a broad range of bacteria, even under high-salt conditions (Cantisani et al 2014). According to the helical wheel diagram in Fig.…”

Host-defense peptides of the skin with therapeutic potential: From hagfish to human

“…The peptide shows growth-inhibitory activity against a wide range of bacteria and yeast pathogens that is retained in the presence of sodium chloride and the peptide shows no hemolytic activity against mammalian red blood cells at concentrations up to 500 g/ml. Structure-activity studies have led to the design of analogs of myxinidin with increased antimicrobial potency formed by substituting the His 3 , Asp 4 and Pro 11 residues by Arg and adding a Trp residue to the N-terminus [14]. Anticancer, antiviral and immunomodulatory activities of myxinidin and its analogs have not yet been reported but are clearly worthy of investigation.…”