Matching amino acids membrane preference profile to improve activity of antimicrobial peptides

Abstract

Antimicrobial peptides (AMPs) are cationic antibiotics that can kill multidrug-resistant bacteria via membrane insertion. However, their weak activity limits their clinical use. Ironically, the cationic charge of AMPs is essential for membrane binding, but it obstructs membrane insertion. In this study, we postulate that this problem can be overcome by locating cationic amino acids at the energetically preferred membrane surface. All amino acids have an energetically preferred or less preferred membrane position profile, and this profile is strongly related to membrane insertion. However, most AMPs do not follow this profile. One exception is protegrin-1, a powerful but neglected AMP. In the present study, we found that a potent AMP, WCopW5, strongly resembles protegrin-1 and that the match between its sequence and the preferred position profile closely correlates with its antimicrobial activity. One of its derivatives, WCopW43, has antimicrobial activity comparable to that of the most effective AMPs in clinical use.

Insights into the Adsorption Mechanisms of the Antimicrobial Peptide CIDEM-501 on Membrane Models

“…Polar residues such as Arg13, Arg14, Arg24, and Arg25 allow the approximation of the peptide to the surface membrane helped by electrostatic attraction. On the other hand, several studies have emphasized the preference of the aromatics residues for the interfaces between membrane surfaces and the center, allowing them to act as anchors for the AMPs and proteins [52][53][54].…”

Possible Molecular Mechanisms Underlying the Decrease in the Antibacterial Activity of Protamine-like Proteins after Exposure of Mytilus galloprovincialis to Chromium and Mercury

“…This amino acid can interact both electrostatically and by forming hydrogen bonds with the negatively charged phospholipids of the bacterial cell membrane [30,31]. It is well known that positive charges are essential for antibacterial activity because they allow protein-membrane interactions, but at the same time, they represent a steric encumbrance for crossing the bacterial membrane [32,33]. The increased fluorescence of PLs observed under the conditions of exposure to the highest concentrations (100 pM HgCl 2 and 100 nM Cr(VI)) could be responsible for the higher MIC and MBC values obtained for the PLs of mussels in these conditions.…”

Engineering the interaction of short antimicrobial peptides with bacterial barriers

“…[13][14][15] Despite the definition of design rules and the high number of AMPs discovered to date, their translation into the clinic is still slow, and several limitations hamper their confirmation as new therapeutics. 8,[16][17][18] Among them, high cost of production, when compared to classical antibiotics, and susceptibility to proteases represent critical issues. The cost-effectiveness of AMPs could potentially be improved by decreasing the length of the polypeptide sequences.…”