Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783621713950408704 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7730571 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT tzengshiouru acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT huangyiwei acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT zhangyaoqing acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT yangchingyi acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chienhansheng acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chenyiru acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT yusungliang acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chenchings acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chiuhaochieh acelecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT tzengshiouru celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT huangyiwei celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT zhangyaoqing celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT yangchingyi celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chienhansheng celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chenyiru celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT yusungliang celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chenchings celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase AT chiuhaochieh celecoxibderivativeeradicatesantibioticresistantstaphylococcusaureusandbiofilmsbytargetingyidc2translocase |