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A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase

The treatment of Staphylococcus aureus infections is impeded by the prevalence of MRSA and the formation of persisters and biofilms. Previously, we identified two celecoxib derivatives, Cpd36 and Cpd46, to eradicate MRSA and other staphylococci. Through whole-genome resequencing, we obtained several...

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Autores principales: Tzeng, Shiou-Ru, Huang, Yi-Wei, Zhang, Yao-Qing, Yang, Ching-Yi, Chien, Han-Sheng, Chen, Yi-Ru, Yu, Sung-Liang, Chen, Ching S., Chiu, Hao-Chieh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730571/
https://www.ncbi.nlm.nih.gov/pubmed/33297331
http://dx.doi.org/10.3390/ijms21239312
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author Tzeng, Shiou-Ru
Huang, Yi-Wei
Zhang, Yao-Qing
Yang, Ching-Yi
Chien, Han-Sheng
Chen, Yi-Ru
Yu, Sung-Liang
Chen, Ching S.
Chiu, Hao-Chieh
author_facet Tzeng, Shiou-Ru
Huang, Yi-Wei
Zhang, Yao-Qing
Yang, Ching-Yi
Chien, Han-Sheng
Chen, Yi-Ru
Yu, Sung-Liang
Chen, Ching S.
Chiu, Hao-Chieh
author_sort Tzeng, Shiou-Ru
collection PubMed
description The treatment of Staphylococcus aureus infections is impeded by the prevalence of MRSA and the formation of persisters and biofilms. Previously, we identified two celecoxib derivatives, Cpd36 and Cpd46, to eradicate MRSA and other staphylococci. Through whole-genome resequencing, we obtained several lines of evidence that these compounds might act by targeting the membrane protein translocase YidC2. Our data showed that ectopic expression of YidC2 in S. aureus decreased the bacterial susceptibility to Cpd36 and Cpd46, and that the YidC2-mediated tolerance to environmental stresses was suppressed by both compounds. Moreover, the membrane translocation of ATP synthase subunit c, a substrate of YidC2, was blocked by Cpd46, leading to a reduction in bacterial ATP production. Furthermore, we found that the thermal stability of bacterial YidC2 was enhanced, and introducing point mutations into the substrate-interacting cavity of YidC2 had a dramatic effect on Cpd36 binding via surface plasmon resonance assays. Finally, we demonstrated that these YidC2 inhibitors could effectively eradicate MRSA persisters and biofilms. Our findings highlight the potential of impeding YidC2-mediated translocation of membrane proteins as a new strategy for the treatment of bacterial infections.
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spelling pubmed-77305712020-12-12 A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase Tzeng, Shiou-Ru Huang, Yi-Wei Zhang, Yao-Qing Yang, Ching-Yi Chien, Han-Sheng Chen, Yi-Ru Yu, Sung-Liang Chen, Ching S. Chiu, Hao-Chieh Int J Mol Sci Article The treatment of Staphylococcus aureus infections is impeded by the prevalence of MRSA and the formation of persisters and biofilms. Previously, we identified two celecoxib derivatives, Cpd36 and Cpd46, to eradicate MRSA and other staphylococci. Through whole-genome resequencing, we obtained several lines of evidence that these compounds might act by targeting the membrane protein translocase YidC2. Our data showed that ectopic expression of YidC2 in S. aureus decreased the bacterial susceptibility to Cpd36 and Cpd46, and that the YidC2-mediated tolerance to environmental stresses was suppressed by both compounds. Moreover, the membrane translocation of ATP synthase subunit c, a substrate of YidC2, was blocked by Cpd46, leading to a reduction in bacterial ATP production. Furthermore, we found that the thermal stability of bacterial YidC2 was enhanced, and introducing point mutations into the substrate-interacting cavity of YidC2 had a dramatic effect on Cpd36 binding via surface plasmon resonance assays. Finally, we demonstrated that these YidC2 inhibitors could effectively eradicate MRSA persisters and biofilms. Our findings highlight the potential of impeding YidC2-mediated translocation of membrane proteins as a new strategy for the treatment of bacterial infections. MDPI 2020-12-07 /pmc/articles/PMC7730571/ /pubmed/33297331 http://dx.doi.org/10.3390/ijms21239312 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tzeng, Shiou-Ru
Huang, Yi-Wei
Zhang, Yao-Qing
Yang, Ching-Yi
Chien, Han-Sheng
Chen, Yi-Ru
Yu, Sung-Liang
Chen, Ching S.
Chiu, Hao-Chieh
A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title_full A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title_fullStr A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title_full_unstemmed A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title_short A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase
title_sort celecoxib derivative eradicates antibiotic-resistant staphylococcus aureus and biofilms by targeting yidc2 translocase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730571/
https://www.ncbi.nlm.nih.gov/pubmed/33297331
http://dx.doi.org/10.3390/ijms21239312
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