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Article

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

1
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
2
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 10048, Taiwan
3
Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
4
Drug Development Center, China Medical University, Taichung 40402, Taiwan
5
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(23), 9312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239312
Received: 27 October 2020 / Revised: 26 November 2020 / Accepted: 3 December 2020 / Published: 7 December 2020
(This article belongs to the Special Issue Microbial Biofilms and Antibiofilm Agents)
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. View Full-Text
Keywords: MRSA; translocon; thermal shift; surface plasmon resonance MRSA; translocon; thermal shift; surface plasmon resonance
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MDPI and ACS Style

Tzeng, S.-R.; Huang, Y.-W.; Zhang, Y.-Q.; Yang, C.-Y.; Chien, H.-S.; Chen, Y.-R.; Yu, S.-L.; Chen, C.S.; Chiu, H.-C. A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase. Int. J. Mol. Sci. 2020, 21, 9312. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239312

AMA Style

Tzeng S-R, Huang Y-W, Zhang Y-Q, Yang C-Y, Chien H-S, Chen Y-R, Yu S-L, Chen CS, Chiu H-C. A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase. International Journal of Molecular Sciences. 2020; 21(23):9312. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239312

Chicago/Turabian Style

Tzeng, Shiou-Ru, Yi-Wei Huang, Yao-Qing Zhang, Ching-Yi Yang, Han-Sheng Chien, Yi-Ru Chen, Sung-Liang Yu, Ching S. Chen, and Hao-Chieh Chiu. 2020. "A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase" International Journal of Molecular Sciences 21, no. 23: 9312. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239312

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