Mechanism of action of novel synthetic dodecapeptides against Candida albicans.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS AND CONCLUSIONS:

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.

GENERAL SIGNIFICANCE:

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.

• Authors: Indresh Kumar Maurya, Chaitanya Kumar Thota, Jyotsna Sharma, Santosh Genba Tupe, Preeti Chaudhary, Manoj Kumar Singh, Indu Shekhar Thakur, Mukund Deshpande, Rajendra Prasad, Virander Singh Chauhan
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1830 Issue 11 Pg. 5193-203 (Nov 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23876294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Antifungal Agents
• Echinocandins
• Lipopeptides
• Peptides
• Reactive Oxygen Species
• Fluconazole
• Caspofungin

Topics

• Antifungal Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Candida albicans (drug effects)
• Caspofungin
• Cell Membrane Permeability (drug effects)
• Cell Wall (drug effects, metabolism)
• Drug Synergism
• Echinocandins (pharmacology)
• Fluconazole (pharmacology)
• Hemolysis (drug effects)
• Lipopeptides
• Necrosis (drug therapy, metabolism)
• Peptides (chemical synthesis, pharmacology)
• Reactive Oxygen Species (metabolism)