Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane

Sk Abdul Mohid; Karishma Biswas; Tae Jun Won; Lakshmi S. Mallela; Arin Gucchait; Lena Butzke; Riddhiman Sarkar; Timothy Barkham; Bernd Reif; Enrico Leipold; Sanhita Roy; Anup K. Misra; Rajamani Lakshminarayanan; Dong Kuk Lee; Anirban Bhunia

doi:10.1016/j.bbamem.2022.183996

Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane

Sk Abdul Mohid, Karishma Biswas, Tae Jun Won, Lakshmi S. Mallela, Arin Gucchait, Lena Butzke, Riddhiman Sarkar, Timothy Barkham, Bernd Reif, Enrico Leipold, Sanhita Roy, Anup K. Misra, Rajamani Lakshminarayanan, Dong Kuk Lee^*, Anirban Bhunia

^*Corresponding author for this work

19 Citations (Scopus)

Abstract

The treatment of invasive drug-resistant and potentially life-threatening fungal infections is limited to few therapeutic options that are usually associated with severe side effects. The development of new effective antimycotics with a more tolerable side effect profile is therefore of utmost clinical importance. Here, we used a combination of complementary in vitro assays and structural analytical methods to analyze the interaction of the de novo antimicrobial peptide VG16KRKP with the sterol moieties of biological cell membranes. We demonstrate that VG16KRKP disturbs the structural integrity of fungal membranes both in vitro and in model membrane system containing ergosterol along with phosphatidylethanolamine lipid and exhibits broad-spectrum antifungal activity. As revealed by systematic structure-function analysis of mutated VG16KRKP analogs, a specific pattern of basic and hydrophobic amino acid side chains in the primary peptide sequence determines the selectivity of VG16KRKP for fungal specific membranes.

Original language	English
Article number	183996
Journal	Biochimica et Biophysica Acta - Biomembranes
Volume	1864
Issue number	10
ISSN	0005-2736
DOIs	https://doi.org/10.1016/j.bbamem.2022.183996
Publication status	Published - 01.10.2022

Funding

This research was partly supported by Science and Engineering Research Board (File No. EMR/2017/003457 to AB), and partly by Bose Institute intramural external research fund (to AB). SAM, KB and AG thank Bose Institute, CSIR-UGC, CSIR Govt. of India, respectively for providing Fellowship. DKL was supported through the Korea Environmental Industry & Technology Institute (KEITI) with the resources funded by the Ministry of Environment in 2020. RL thanks Singapore Ministry of Health's National Medical Research Council (INCEPTOR)-NMRC/CG/M010/2017_SERI and the SingHealth Foundation ( SHF/FG663P/2017 ) for financial support. This research was partly supported by Science and Engineering Research Board (File No. EMR/2017/003457 to AB), and partly by Bose Institute intramural external research fund (to AB). SAM, KB and AG thank Bose Institute, CSIR-UGC, CSIR Govt. of India, respectively for providing Fellowship. DKL was supported through the Korea Environmental Industry & Technology Institute (KEITI) with the resources funded by the Ministry of Environment in 2020. RL thanks Singapore Ministry of Health's National Medical Research Council (INCEPTOR)-NMRC/CG/M010/2017_SERI and the SingHealth Foundation (SHF/FG663P/2017) for financial support.

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10.1016/j.bbamem.2022.183996

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Mohid, S. A., Biswas, K., Won, T. J., Mallela, L. S., Gucchait, A., Butzke, L., Sarkar, R., Barkham, T., Reif, B., Leipold, E., Roy, S., Misra, A. K., Lakshminarayanan, R., Lee, D. K., & Bhunia, A. (2022). Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane. Biochimica et Biophysica Acta - Biomembranes, 1864(10), Article 183996. https://doi.org/10.1016/j.bbamem.2022.183996

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title = "Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane",

abstract = "The treatment of invasive drug-resistant and potentially life-threatening fungal infections is limited to few therapeutic options that are usually associated with severe side effects. The development of new effective antimycotics with a more tolerable side effect profile is therefore of utmost clinical importance. Here, we used a combination of complementary in vitro assays and structural analytical methods to analyze the interaction of the de novo antimicrobial peptide VG16KRKP with the sterol moieties of biological cell membranes. We demonstrate that VG16KRKP disturbs the structural integrity of fungal membranes both in vitro and in model membrane system containing ergosterol along with phosphatidylethanolamine lipid and exhibits broad-spectrum antifungal activity. As revealed by systematic structure-function analysis of mutated VG16KRKP analogs, a specific pattern of basic and hydrophobic amino acid side chains in the primary peptide sequence determines the selectivity of VG16KRKP for fungal specific membranes.",

author = "Mohid, \{Sk Abdul\} and Karishma Biswas and Won, \{Tae Jun\} and Mallela, \{Lakshmi S.\} and Arin Gucchait and Lena Butzke and Riddhiman Sarkar and Timothy Barkham and Bernd Reif and Enrico Leipold and Sanhita Roy and Misra, \{Anup K.\} and Rajamani Lakshminarayanan and Lee, \{Dong Kuk\} and Anirban Bhunia",

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Mohid, SA, Biswas, K, Won, TJ, Mallela, LS, Gucchait, A, Butzke, L, Sarkar, R, Barkham, T, Reif, B, Leipold, E, Roy, S, Misra, AK, Lakshminarayanan, R, Lee, DK & Bhunia, A 2022, 'Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane', Biochimica et Biophysica Acta - Biomembranes, vol. 1864, no. 10, 183996. https://doi.org/10.1016/j.bbamem.2022.183996

TY - JOUR

T1 - Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane

AU - Mohid, Sk Abdul

AU - Biswas, Karishma

AU - Won, Tae Jun

AU - Mallela, Lakshmi S.

AU - Gucchait, Arin

AU - Butzke, Lena

AU - Sarkar, Riddhiman

AU - Barkham, Timothy

AU - Reif, Bernd

AU - Leipold, Enrico

AU - Roy, Sanhita

AU - Misra, Anup K.

AU - Lakshminarayanan, Rajamani

AU - Lee, Dong Kuk

AU - Bhunia, Anirban

PY - 2022/10/1

Y1 - 2022/10/1

N2 - The treatment of invasive drug-resistant and potentially life-threatening fungal infections is limited to few therapeutic options that are usually associated with severe side effects. The development of new effective antimycotics with a more tolerable side effect profile is therefore of utmost clinical importance. Here, we used a combination of complementary in vitro assays and structural analytical methods to analyze the interaction of the de novo antimicrobial peptide VG16KRKP with the sterol moieties of biological cell membranes. We demonstrate that VG16KRKP disturbs the structural integrity of fungal membranes both in vitro and in model membrane system containing ergosterol along with phosphatidylethanolamine lipid and exhibits broad-spectrum antifungal activity. As revealed by systematic structure-function analysis of mutated VG16KRKP analogs, a specific pattern of basic and hydrophobic amino acid side chains in the primary peptide sequence determines the selectivity of VG16KRKP for fungal specific membranes.

AB - The treatment of invasive drug-resistant and potentially life-threatening fungal infections is limited to few therapeutic options that are usually associated with severe side effects. The development of new effective antimycotics with a more tolerable side effect profile is therefore of utmost clinical importance. Here, we used a combination of complementary in vitro assays and structural analytical methods to analyze the interaction of the de novo antimicrobial peptide VG16KRKP with the sterol moieties of biological cell membranes. We demonstrate that VG16KRKP disturbs the structural integrity of fungal membranes both in vitro and in model membrane system containing ergosterol along with phosphatidylethanolamine lipid and exhibits broad-spectrum antifungal activity. As revealed by systematic structure-function analysis of mutated VG16KRKP analogs, a specific pattern of basic and hydrophobic amino acid side chains in the primary peptide sequence determines the selectivity of VG16KRKP for fungal specific membranes.

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DO - 10.1016/j.bbamem.2022.183996

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SN - 0005-2736

VL - 1864

JO - Biochimica et Biophysica Acta - Biomembranes

JF - Biochimica et Biophysica Acta - Biomembranes

IS - 10

M1 - 183996

ER -

Structural insights into the interaction of antifungal peptides and ergosterol containing fungal membrane

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