title: Mode of Action of a Designed Antimicrobial Peptide: High Potency against Cryptococcus neoformans.
abstract: There is a significant need for developing compounds that kill Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis in immunocompromised individuals. Here, we report the mode of action of a designed antifungal peptide, VG16KRKP (VARGWKRKCPLFGKGG) against C. neoformans. It is shown that VG16KRKP kills fungal cells mainly through membrane compromise leading to efflux of ions and cell metabolites. Intracellular localization, inhibition of in vitro transcription, and DNA binding suggest a secondary mode of action for the peptide, hinting at possible intracellular targets. Atomistic structure of the peptide determined by NMR experiments on live C. neoformans cells reveals an amphipathic arrangement stabilized by hydrophobic interactions among A2, W5, and F12, a conventional folding pattern also known to play a major role in peptide-mediated Gram-negative bacterial killing, revealing the importance of this motif. These structural details in the context of live cell provide valuable insights into the design of potent peptides for effective treatment of human and plant fungal infections.
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India.
authors.forename: Aritreyee
authors.initials: A
authors.lastname: Datta
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Korea.
authors.forename: Jaesun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India.
authors.forename: Dipita
authors.initials: D
authors.lastname: Bhattacharyya
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India.
authors.forename: Rajiv K
authors.initials: RK
authors.lastname: Kar
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India.
authors.forename: Humaira
authors.initials: H
authors.lastname: Ilyas
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, India.
authors.forename: Arkajyoti
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Korea.
authors.forename: Eunseol
authors.initials: E
authors.lastname: An
authors.affiliation: Department of Chemistry, Bose Institute, Kolkata, India.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Korea.
authors.forename: Dongkuk
authors.initials: D
authors.lastname: Lee
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Sanyal
authors.affiliation: Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata, India. Electronic address: anirbanbhunia@gmail.com.
authors.forename: Anirban
authors.initials: A
authors.lastname: Bhunia
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000166:cytology / Q000187:drug effects*; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009690:Nucleic Acid Conformation
chemical_list: D023181:Antimicrobial Cationic Peptides; D004247:DNA