Mechanism of action of novel synthetic dodecapeptides against Candida albicans

• Published in: Biochimica et biophysica acta Vol. 1830; no. 11; pp. 5193 - 5203
• Main Authors: Maurya, Indresh Kumar, Thota, Chaitanya Kumar, Sharma, Jyotsna, Tupe, Santosh Genba, Chaudhary, Preeti, Singh, Manoj Kumar, Thakur, Indu Shekhar, Deshpande, Mukund, Prasad, Rajendra, Chauhan, Virander Singh
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2013
• Subjects: amino acids; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antifungal peptide; antifungal properties; Antimicrobial peptide (AMP); antimicrobial peptides; Apoptosis; Apoptosis - drug effects; Candida albicans; Candida albicans - drug effects; caspofungin; Cell Membrane Permeability - drug effects; Cell Wall - drug effects; Cell Wall - metabolism; cell walls; confocal microscopy; Drug Synergism; Echinocandins - pharmacology; flow cytometry; fluconazole; Fluconazole - pharmacology; fluorometry; Hemolysis - drug effects; Lipopeptides; mechanism of action; membrane permeability; minimum inhibitory concentration; molecular weight; necrosis; Necrosis - drug therapy; Necrosis - metabolism; pathogens; Peptides - chemical synthesis; Peptides - pharmacology; reactive oxygen species; Reactive Oxygen Species (ROS); Reactive Oxygen Species - metabolism; synergism; transmission electron microscopy; yeasts; Candida albicans; ABC; Antifungal peptide; Reactive Oxygen Species (ROS); ROS; Antimicrobial peptide (AMP); FICI; MDR; SEM; MFS; TEM; Apoptosis; Reactive Oxygen Species; ATP-Binding Cassette; Scanning Electron Microscopy; Major Facilitator Superfamily; Multidrug Resistance; Fraction Inhibitory Concentration Index; Transmission Electron Microscopy
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.07.016

Three de novo designed low molecular weight cationic peptides (IJ2, IJ3 and IJ4) containing an unnatural amino acid α,β-didehydrophenylalanine (∆Phe) exhibited potent antifungal activity against fluconazole (FLC) sensitive and resistant clinical isolates of Candida albicans as well as non-albicans and other yeast and filamentous pathogenic fungi. In the present study, their synthesis, susceptibility of different fungi and the mechanism of anti-candidal action have been elucidated. The antimicrobial peptides (AMPs) were synthesized by solid-phase method and checked for antifungal activity against different yeasts and fungi by broth microdilution method. Anti-candidal mode of action of the peptides was investigated through detecting membrane permeabilization by confocal microscopy, Reactive Oxygen Species (ROS) generation by fluorometry, apoptosis and necrosis by flow cytometry and cell wall damage using Scanning and Transmission Electron Microscopy. The MIC of the peptides against C. albicans and other yeast and filamentous fungal pathogens ranged between 3.91 and 250μM. All three peptides exhibited effect on multiple targets in C. albicans including disruption of cell wall structures, compromised cell membrane permeability leading to their enhanced entry into the cells, accumulation of ROS and induction of apoptosis. The peptides also showed synergistic effect when used in combination with fluconazole (FLC) and caspofungin (CAS) against C. albicans. The study suggests that the AMPs alone or in combination with conventional antifungals hold promise for the control of fungal pathogens, and need to be further explored for treatment of fungal infections. •Cationic peptides with amino acid α,β-didehydrophenylalanine were synthesized.•Peptides showed potent antifungal activity against human pathogenic fungi.•Peptides showed synergism with fluconazole/caspofungin against Candida albicans.•Mechanism of anticandidal action of the peptides has been elucidated.