Academic Journal
Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA
| العنوان: | Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA |
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| المؤلفون: | Schäfer, Ann-Britt, Steenhuis, Maurice, Jim, Kin Ki, Neef, Jolanda, O'Keefe, Sarah, Whitehead, Roger C, Swanton, Eileithyia, Wang, Biwen, Halbedel, Sven, High, Stephen, van Dijl, Jan Maarten, Luirink, Joen, Wenzel, Michaela |
| المصدر: | Schäfer , A-B , Steenhuis , M , Jim , K K , Neef , J , O'Keefe , S , Whitehead , R C , Swanton , E , Wang , B , Halbedel , S , High , S , van Dijl , J M , Luirink , J & Wenzel , M 2023 , ' Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA ' , ACS Infectious Diseases , vol. 9 , no. 2 , pp. 253-269 . https://doi.org/10.1021/acsinfecdis.2c00404 |
| سنة النشر: | 2023 |
| المجموعة: | University of Groningen research database |
| مصطلحات موضوعية: | Animals, Escherichia coli/genetics, DNA, Bacterial, Anti-Bacterial Agents/pharmacology, Zebrafish, Gram-Negative Bacteria/metabolism, Gram-Positive Bacteria, Protein Transport |
| الوصف: | Eeyarestatin 24 (ES24) is a promising new antibiotic with broad-spectrum activity. It shares structural similarity with nitrofurantoin (NFT), yet appears to have a distinct and novel mechanism: ES24 was found to inhibit SecYEG-mediated protein transport and membrane insertion in Gram-negative bacteria. However, possible additional targets have not yet been explored. Moreover, its activity was notably better against Gram-positive bacteria, for which its mechanism of action had not yet been investigated. We have used transcriptomic stress response profiling, phenotypic assays, and protein secretion analyses to investigate the mode of action of ES24 in comparison with NFT using the Gram-positive model bacterium Bacillus subtilis and have compared our findings to Gram-negative Escherichia coli. Here, we show the inhibition of Sec-dependent protein secretion in B. subtilis and additionally provide evidence for DNA damage, probably caused by the generation of reactive derivatives of ES24. Interestingly, ES24 caused a gradual dissipation of the membrane potential, which led to delocalization of cytokinetic proteins and subsequent cell elongation in E. coli. However, none of those effects were observed in B. subtilis, thereby suggesting that ES24 displays distinct mechanistic differences with respect to Gram-positive and Gram-negative bacteria. Despite its structural similarity to NFT, ES24 profoundly differed in our phenotypic analysis, which implies that it does not share the NFT mechanism of generalized macromolecule and structural damage. Importantly, ES24 outperformed NFT in vivo in a zebrafish embryo pneumococcal infection model. Our results suggest that ES24 not only inhibits the Sec translocon, but also targets bacterial DNA and, in Gram-negative bacteria, the cell membrane. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1021/acsinfecdis.2c00404 |
| الاتاحة: | https://hdl.handle.net/11370/06ca9767-5908-48ad-9a37-fcb6d4fd4815 https://research.rug.nl/en/publications/06ca9767-5908-48ad-9a37-fcb6d4fd4815 https://doi.org/10.1021/acsinfecdis.2c00404 https://pure.rug.nl/ws/files/576823590/acsinfecdis.2c00404.pdf |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.F70D74A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acsinfecdis.2c00404 |
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