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 De 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; Danielle A. Garsin

doi:10.1038/s41467-022-33613-1

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 De 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, Danielle A. Garsin

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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.

Original language	English (US)
Article number	6047
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33613-1
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Cruz, M. R., Cristy, S., Guha, S., De Cesare, G. B., Evdokimova, E., Sanchez, H., Borek, D., Miramón, P., Yano, J., Fidel, P. L., Savchenko, A., Andes, D. R., Stogios, P. J., Lorenz, M. C., & Garsin, D. A. (2022). Structural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections. Nature communications, 13(1), Article 6047. https://doi.org/10.1038/s41467-022-33613-1

Cruz, MR, Cristy, S, Guha, S, De Cesare, GB, Evdokimova, E, Sanchez, H, Borek, D, Miramón, P, Yano, J, Fidel, PL, Savchenko, A, Andes, DR, Stogios, PJ, Lorenz, MC & Garsin, DA 2022, 'Structural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections', Nature communications, vol. 13, no. 1, 6047. https://doi.org/10.1038/s41467-022-33613-1

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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.",

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AU - Miramón, Pedro

AU - Yano, Junko

AU - Fidel, Paul L.

AU - Savchenko, Alexei

AU - Andes, David R.

AU - Stogios, Peter J.

AU - Lorenz, Michael C.

AU - Garsin, Danielle A.

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

Abstract

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