Synthetic Multivalent Antifungal Peptides Effective against Fungi

Abstract

Taking advantage of the cluster effect observed in multivalent peptides, this work describes antifungal activity and possible mechanism of action of tetravalent peptide (B4010) which carries 4 copies of the sequence RGRKVVRR through a branched lysine core. B4010 displayed better antifungal properties than natamycin and amphotericin B. The peptide retained significant activity in the presence of monovalent/divalent cations, trypsin and serum and tear fluid. Moreover, B4010 is non-haemolytic and non-toxic to mice by intraperitoneal (200 mg/kg) or intravenous (100 mg/kg) routes. S. cerevisiae mutant strains with altered membrane sterol structures and composition showed hyper senstivity to B4010. The peptide had no affinity for cell wall polysaccharides and caused rapid dissipation of membrane potential and release of vital ions and ATP when treated with C. albicans. We demonstrate that additives which alter the membrane potential or membrane rigidity protect C. albicans from B4010-induced lethality. Calcein release assay and molecular dynamics simulations showed that the peptide preferentially binds to mixed bilayer containing ergosterol over phophotidylcholine-cholesterol bilayers. The studies further suggested that the first arginine is important for mediating peptide-bilayer interactions. Replacing the first arginine led to a 2–4 fold decrease in antifungal activities and reduced membrane disruption properties. The combined in silico and in vitro approach should facilitate rational design of new tetravalent antifungal peptides.

Insight into membrane selectivity of linear and branched polyethylenimines and their potential as biocides for advanced wound dressings

“…Bacterial viability assay performed in parallel with the membrane potential dissipation assay further confirm that the loss of membrane potential is associated with bacterial lethality, thus demonstrating the membrane-targeting antimicrobial activity of the cationic polymers (Fig. S4c) [55][56][57][58][59]. Next, we examined the cytotoxicity of the polymers for the human telomerase-immortalized corneal epithelial cells (hTCEpi) by real time xCELLigence cell index (CI) impedance measurements.…”

Effectiveness of Antimicrobial Peptide Immobilization for Preventing Perioperative Cornea Implant-Associated Bacterial Infection

“…Previous studies have indicated that incubation of the full-length peptide with trypsin generates a number of proteolytically processed fragments and a partial loss of antimicrobial activities in the presence of tear fluid (32). Since the microenvironment in the stroma encompasses a number of proteases, we sought to investigate the efficacy of the full-length SESB2V peptide and its various sequentially truncated variants.…”

Concatemerization increases the inhibitory activity of short, cell-penetrating, cationic and tryptophan-rich antifungal peptides

“…Therefore, increase of activity is likely a consequence of the molar increase of physically linked AMP units per molecule of peptide, and not of any significant change in the mechanism of action. Increased antimicrobial activity was also associated with longer antifungal peptides in the case of the concatemer series of (RW) and (KW) dimeric peptides (Gopal et al 2012) or of a tetramer b r a n c h e d d e r i v a t i v e o f B 4 0 1 0 ( R G R K V V R R ) (Lakshminarayanan et al 2014), as well as in the antibacterial repeats of BP100 (Badosa et al 2013), although no mechanistic data were reported in these studies.…”