Abstract

CATIONIC ANTIFUNGAL PEPTIDES MAY CLUSTER ERGOSTEROLS TO WEAKEN FUNGAL CELL MEMBRANE

Ruchi Omar, Sweta Sharma and Arpita Yadav*

ABSTRACT

This study describes our efforts in understanding mechanistic aspects of non-conventional cationic peptides as antifungal agents and how their pharmacokinetic properties may be enhanced to bring these natural, safe compounds to drug market. The study illustrates for the first time depletion of ergosterol levels by these peptides prior to its incorporation in fungal cell membrane lipid raft resulting in an effect similar to inhibition of 14α-demethylase enzyme and weakened fungal cell membranes prone to lysis. This mode of action is different as compared to the previously accepted membrane disruptive mechanism where the antifungal agent interacts with the phospholipid cell membrane resulting in pore formation. This study also depicts that introduction of artificial backbone in moderately cationic peptide with appropriate combination of amino acid residues and conformation may help overcome pharmacokinetic issues related to these antifungal lead compounds. The multiple synergistic mode of action of these compounds renders them at an advantage over other antifungal agents. This study is expected to incubate synthetic efforts in this direction which would definitely help bring these non-toxic compounds in clinical use.

Keywords: 14?-demethylase, indirect inhibition, cationic peptide, antifungal, artificial backbone, ergosterol, ntermolecular interaction, Hartree –Fock.