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Structural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections

Author

Listed:
  • Melissa R. Cruz

    (The University of Texas Health Science Center at Houston)

  • Shane Cristy

    (The University of Texas Health Science Center at Houston)

  • Shantanu Guha

    (The University of Texas Health Science Center at Houston)

  • Giuseppe Buda Cesare

    (The University of Texas Health Science Center at Houston)

  • Elena Evdokimova

    (University of Toronto)

  • Hiram Sanchez

    (University of Wisconsin
    University of Wisconsin)

  • Dominika Borek

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Pedro Miramón

    (The University of Texas Health Science Center at Houston)

  • Junko Yano

    (Louisiana State University Health School of Dentistry)

  • Paul L. Fidel

    (Louisiana State University Health School of Dentistry)

  • Alexei Savchenko

    (University of Toronto
    Immunology and Infectious Diseases, University of Calgary
    Center for Structural Genomics of Infectious Diseases (CSGID))

  • David R. Andes

    (University of Wisconsin
    University of Wisconsin)

  • Peter J. Stogios

    (University of Toronto)

  • Michael C. Lorenz

    (The University of Texas Health Science Center at Houston)

  • Danielle A. Garsin

    (The University of Texas Health Science Center at Houston)

Abstract

Fungal pathogens are a continuing challenge due to few effective antifungals and a rise in resistance. In previous work, we described the inhibition of Candida albicans virulence following exposure to the 68 amino acid bacteriocin, EntV, secreted by Enterococcus faecalis. Here, to optimize EntV as a potential therapeutic and better understand its antifungal features, an X-ray structure is obtained. The structure consists of six alpha helices enclosing a seventh 16 amino acid helix (α7). The individual helices are tested for antifungal activity using in vitro and nematode infection assays. Interestingly, α7 retains antifungal, but not antibacterial activity and is also effective against Candida auris and Cryptococcus neoformans. Further reduction of α7 to 12 amino acids retains full antifungal activity, and excellent efficacy is observed in rodent models of C. albicans oropharyngeal, systemic, and venous catheter infections. Together, these results showcase EntV-derived peptides as promising candidates for antifungal therapeutic development.

Suggested Citation

  • Melissa R. Cruz & Shane Cristy & Shantanu Guha & Giuseppe Buda Cesare & Elena Evdokimova & Hiram Sanchez & Dominika Borek & Pedro Miramón & Junko Yano & Paul L. Fidel & Alexei Savchenko & David R. And, 2022. "Structural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33613-1
    DOI: 10.1038/s41467-022-33613-1
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    References listed on IDEAS

    as
    1. David L. Moyes & Duncan Wilson & Jonathan P. Richardson & Selene Mogavero & Shirley X. Tang & Julia Wernecke & Sarah Höfs & Remi L. Gratacap & Jon Robbins & Manohursingh Runglall & Celia Murciano & Ma, 2016. "Candidalysin is a fungal peptide toxin critical for mucosal infection," Nature, Nature, vol. 532(7597), pages 64-68, April.
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