TY - JOUR
T1 - Mode of Action of a Designed Antimicrobial Peptide
T2 - High Potency against Cryptococcus neoformans
AU - Datta, Aritreyee
AU - Yadav, Vikas
AU - Ghosh, Anirban
AU - Choi, Jaesun
AU - Bhattacharyya, Dipita
AU - Kar, Rajiv K.
AU - Ilyas, Humaira
AU - Dutta, Arkajyoti
AU - An, Eunseol
AU - Mukhopadhyay, Jayanta
AU - Lee, Dongkuk
AU - Sanyal, Kaustuv
AU - Ramamoorthy, Ayyalusamy
AU - Bhunia, Anirban
N1 - Publisher Copyright:
© 2016 Biophysical Society
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84994885254
U2 - 10.1016/j.bpj.2016.08.032
DO - 10.1016/j.bpj.2016.08.032
M3 - Article
C2 - 27760359
AN - SCOPUS:84994885254
SN - 0006-3495
VL - 111
SP - 1724
EP - 1737
JO - Biophysical Journal
JF - Biophysical Journal
IS - 8
ER -