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Dual Action of Eeya...
Dual Action of Eeyarestatin 24 on Sec-Dependent Protein Secretion and Bacterial DNA
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- Schäfer, Ann-Britt, 1993 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Steenhuis, Maurice (författare)
- Vrije Universiteit Amsterdam (VU)
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- Jim, Kin Ki (författare)
- Universiteit Van Amsterdam,University of Amsterdam
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- Neef, Jolanda (författare)
- Rijksuniversiteit Groningen,University of Groningen
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- O’Keefe, Sarah (författare)
- University of Manchester
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- Whitehead, Roger C. (författare)
- University of Manchester
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- Swanton, Eileithyia (författare)
- University of Manchester
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- Wang, Biwen (författare)
- Swammerdam Institute for Life Sciences
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- Halbedel, Sven (författare)
- Otto von Guericke Universitaet Magdeburg
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- High, Stephen (författare)
- University of Manchester
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- van Dijl, Jan Maarten (författare)
- Rijksuniversiteit Groningen,University of Groningen
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- Luirink, Joen (författare)
- Vrije Universiteit Amsterdam (VU)
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- Wenzel, Michaela, 1986 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology
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(creator_code:org_t)
- 2023-01-13
- 2023
- Engelska.
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Ingår i: ACS Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 9:2, s. 253-269
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https://research.cha... (primary) (free)
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https://research.cha...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Nyckelord
- in vivo efficacy
- antibiotic
- protein secretion
- nitrofurantoin
- mechanism of action
- eeyarestatin 24
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Schäfer, Ann-Bri ...
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Steenhuis, Mauri ...
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Jim, Kin Ki
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Neef, Jolanda
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O’Keefe, Sarah
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Whitehead, Roger ...
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visa fler...
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Swanton, Eileith ...
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Wang, Biwen
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Halbedel, Sven
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High, Stephen
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van Dijl, Jan Ma ...
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Luirink, Joen
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Wenzel, Michaela ...
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visa färre...
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- NATURVETENSKAP
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och Biologi
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och Biokemi och mole ...
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- NATURVETENSKAP
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och Biologi
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och Mikrobiologi
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ACS Infectious D ...
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Chalmers tekniska högskola