Structural characterization and biological activity of Crabrolin peptide isoforms with different positive charge.

The search of antimicrobial peptides (AMP) as candidates for the development of antibiotics is an active research field. In this paper we investigated the role of charged residues in antimicrobial activity by using as a template the previously characterized crabrolin peptide. Mutant peptides in which the charge was diminished (Crabrolin Minus) or increased (Crabrolin Plus) were assayed for their ability to inhibit bacterial growth and to bind model bacterial membranes or lipopolysaccharide (LPS). Structural analysis of both peptides by means of CD, NMR and Molecular Dynamics was also performed and correlated to the biological data. Although native Crabrolin (WT) displays smaller efficacy than other antibacterial peptides with similar length, Crabrolin Plus displays a significant antimicrobial activity while Crabrolin Minus is not active, thus confirming the key role of the positive charge for interacting with the bacterial membrane. Moreover, our results show that charge position has no effect on the helical propensity of the peptides but drastically affects their antimicrobial activity. Antimicrobial activity versus Gram-positive and Gram-negative bacteria, as well as specific interaction with LPS, suggest multiple binding modes for the active peptide.

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