Synthetic multivalent antifungal peptides effective against fungi

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 propertie...

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Bibliographic Details
Published in:PloS one 2014-02, Vol.9 (2), p.e87730
Main Authors: Lakshminarayanan, Rajamani, Liu, Shouping, Li, Jianguo, Nandhakumar, Muruganantham, Aung, Thet Tun, Goh, Eunice, Chang, Jamie Ya Ting, Saraswathi, Padhmanaban, Tang, Charles, Safie, Siti Radiah Binte, Lin, Lim Yih, Riezman, Howard, Lei, Zhou, Verma, Chandra S, Beuerman, Roger W
Format: Article
Language:English
Subjects:
Additives
Amphotericin B
Animals
Antifungal activity
Antifungal Agents - pharmacology
Arginine
Bioinformatics
Biology
Calcein
Calorimetry
Candida albicans
Candida albicans - drug effects
Candida albicans - growth & development
Candida albicans - metabolism
Cations
Cell Membrane - metabolism
Cell walls
Cells, Cultured
Cholesterol
Circular Dichroism
Conjunctiva - cytology
Conjunctiva - drug effects
Conjunctiva - metabolism
Divalent cations
Drug resistance
Electrophoresis, Polyacrylamide Gel
Epidemiology
Epithelial Cells - cytology
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Ergosterol
Fungi
Fungicides
Gram-positive bacteria
Hemolysis - drug effects
Humans
Intravenous administration
Lethality
Lipid Bilayers - metabolism
Lipids
Lysine
Medical schools
Medicine
Membrane potential
Mice
Mice, Inbred C57BL
Microbial Sensitivity Tests
Molecular dynamics
Molecular Dynamics Simulation
Natamycin
Neurosciences
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptides
Physiology
Phytosterols
Plant lipids
Polysaccharides
Rabbits
Rigidity
Saccharides
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - growth & development
Saccharomyces cerevisiae - metabolism
Simulation
Tearing
Tropical diseases
Trypsin
Wound Healing - drug effects
Yeast
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0087730