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Mechanism of action of novel synthetic dodecapeptides against Candida albicans
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
Institution:1. Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India;2. International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India;3. Biochemical Sciences Division, National Chemical Laboratory, Pune 411008, India;4. School of Environmental Sciences, Jawaharlal Nehru University, New Delhi 110067, India
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 250 μM. 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.
Keywords:ABC  ATP-Binding Cassette  MFS  Major Facilitator Superfamily  MDR  Multidrug Resistance  SEM  Scanning Electron Microscopy  TEM  Transmission Electron Microscopy  FICI  Fraction Inhibitory Concentration Index  ROS  Reactive Oxygen Species
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