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

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. Andes, Peter J. Stogios, Michael C. Lorenz () and Danielle A. Garsin ()
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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
Dominika Borek: 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
David R. Andes: 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

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33613-1

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