TY - JOUR
T1 - Structural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections
AU - Cruz, Melissa R.
AU - Cristy, Shane
AU - Guha, Shantanu
AU - De Cesare, Giuseppe Buda
AU - Evdokimova, Elena
AU - Sanchez, Hiram
AU - Borek, Dominika
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.
N1 - Funding Information:
We thank Youngchang Kim, Structural Biology Center, Advanced Photon Source, Argonne National Laboratory, for X-ray diffraction data collection and Rosa Di Leo for cloning. Additionally, we thank Armand Brown and Karan Kaval for valuable discussions. This work was funded by the U.S. National Institutes of Health grant numbers R01DE027608 to DAG and MCL, R01AI073289 to DRA, and T32AI141349 to SG. The crystal structure solved in this work was also funded by the National Institutes of Health under contract No. HHSN272201700060C (Center for Structural Genomics of Infectious Diseases (CSGID); http://csgid.org ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank Youngchang Kim, Structural Biology Center, Advanced Photon Source, Argonne National Laboratory, for X-ray diffraction data collection and Rosa Di Leo for cloning. Additionally, we thank Armand Brown and Karan Kaval for valuable discussions. This work was funded by the U.S. National Institutes of Health grant numbers R01DE027608 to DAG and MCL, R01AI073289 to DRA, and T32AI141349 to SG. The crystal structure solved in this work was also funded by the National Institutes of Health under contract No. HHSN272201700060C (Center for Structural Genomics of Infectious Diseases (CSGID); http://csgid.org). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-022-33613-1
DO - 10.1038/s41467-022-33613-1
M3 - Article
C2 - 36229448
AN - SCOPUS:85139952802
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6047
ER -