Synthetic Multivalent Antifungal Peptides Effective against Fungi

Synthetic Multivalent Antifungal Peptides Effective against Fungi
Title:
Synthetic Multivalent Antifungal Peptides Effective against Fungi
Other Titles:
PLoS One
Keywords:
Publication Date:
03 February 2014
Citation:
Lakshminarayanan R, Liu S, Li J, Nandhakumar M, Aung TT, et al. (2014) Synthetic Multivalent Antifungal Peptides Effective against Fungi. PLoS ONE 9( 2): e87730. doi:10.1371/journal.pone.0087730
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Translational Research Innovations in Ocular Surgery (TRIOS) Programme: Defensins project NMRC/TCR/002-SERI/2008 (RWB) and NMRC/NIG/1020/2010 (RL).
Description:
ISSN:
1932-6203
Files uploaded: