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Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of  bacterial ClpP is an alternative method of discovering antib...

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Autores principales: Wei, Bingyan, Zhang, Tao, Wang, Pengyu, Pan, Yihui, Li, Jiahui, Chen, Weizhong, Zhang, Min, Ji, Quanjiang, Wu, Wenjuan, Lan, Lefu, Gan, Jianhua, Yang, Cai-Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663597/
https://www.ncbi.nlm.nih.gov/pubmed/36376309
http://dx.doi.org/10.1038/s41467-022-34753-0
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author Wei, Bingyan
Zhang, Tao
Wang, Pengyu
Pan, Yihui
Li, Jiahui
Chen, Weizhong
Zhang, Min
Ji, Quanjiang
Wu, Wenjuan
Lan, Lefu
Gan, Jianhua
Yang, Cai-Guang
author_facet Wei, Bingyan
Zhang, Tao
Wang, Pengyu
Pan, Yihui
Li, Jiahui
Chen, Weizhong
Zhang, Min
Ji, Quanjiang
Wu, Wenjuan
Lan, Lefu
Gan, Jianhua
Yang, Cai-Guang
author_sort Wei, Bingyan
collection PubMed
description The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of  bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective  Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.
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spelling pubmed-96635972022-11-15 Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP Wei, Bingyan Zhang, Tao Wang, Pengyu Pan, Yihui Li, Jiahui Chen, Weizhong Zhang, Min Ji, Quanjiang Wu, Wenjuan Lan, Lefu Gan, Jianhua Yang, Cai-Guang Nat Commun Article The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of  bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective  Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections. Nature Publishing Group UK 2022-11-14 /pmc/articles/PMC9663597/ /pubmed/36376309 http://dx.doi.org/10.1038/s41467-022-34753-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wei, Bingyan
Zhang, Tao
Wang, Pengyu
Pan, Yihui
Li, Jiahui
Chen, Weizhong
Zhang, Min
Ji, Quanjiang
Wu, Wenjuan
Lan, Lefu
Gan, Jianhua
Yang, Cai-Guang
Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title_full Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title_fullStr Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title_full_unstemmed Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title_short Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
title_sort anti-infective therapy using species-specific activators of staphylococcus aureus clpp
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9663597/
https://www.ncbi.nlm.nih.gov/pubmed/36376309
http://dx.doi.org/10.1038/s41467-022-34753-0
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