New Antimicrobials Targeting Bacterial RNA Polymerase Holoenzyme Assembly Identified with an in Vivo BRET-Based Discovery Platform Article Swipe
Sara Sartini
,
Elisabetta Levati
,
Martina Maccesi
,
Matteo Guerra
,
Gilberto Spadoni
,
Stéphane Bach
,
Monica Benincasa
,
Marco Scocchi
,
Simone Ottonello
,
Silvia Rivara
,
Barbara Montanini
·
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1021/acschembio.9b00178
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1021/acschembio.9b00178
Bacterial resistance represents a major health threat worldwide, and the development of new therapeutics, including innovative antibiotics, is urgently needed. We describe a discovery platform, centered on in silico screening and in vivo bioluminescence resonance energy transfer in yeast cells, for the identification of new antimicrobials that, by targeting the protein-protein interaction between the β'-subunit and the initiation factor σ70 of bacterial RNA polymerase, inhibit holoenzyme assembly and promoter-specific transcription. Out of 34 000 candidate compounds, we identified seven hits capable of interfering with this interaction. Two derivatives of one of these hits proved to be effective in inhibiting transcription in vitro and growth of the Gram-positive pathogens Staphylococcus aureus and Listeria monocytogenes. Upon supplementation of a permeability adjuvant, one derivative also effectively inhibited Escherichia coli growth. On the basis of the chemical structures of these inhibitors, we generated a ligand-based pharmacophore model that will guide the rational discovery of increasingly effective antibacterial agents.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1021/acschembio.9b00178
- OA Status
- green
- Cited By
- 14
- References
- 36
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2958597446
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2958597446Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1021/acschembio.9b00178Digital Object Identifier
- Title
-
New Antimicrobials Targeting Bacterial RNA Polymerase Holoenzyme Assembly Identified with an in Vivo BRET-Based Discovery PlatformWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2019Year of publication
- Publication date
-
2019-07-16Full publication date if available
- Authors
-
Sara Sartini, Elisabetta Levati, Martina Maccesi, Matteo Guerra, Gilberto Spadoni, Stéphane Bach, Monica Benincasa, Marco Scocchi, Simone Ottonello, Silvia Rivara, Barbara MontaniniList of authors in order
- Landing page
-
https://doi.org/10.1021/acschembio.9b00178Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://hdl.handle.net/11576/2671990Direct OA link when available
- Concepts
-
RNA polymerase, Pharmacophore, In silico, Biology, Drug discovery, Sigma factor, Polymerase, Escherichia coli, In vivo, Transcription (linguistics), Microbiology, Chemistry, Computational biology, Biochemistry, Genetics, Enzyme, Gene, Philosophy, LinguisticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
14Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 4, 2023: 1, 2022: 2, 2021: 4, 2020: 3Per-year citation counts (last 5 years)
- References (count)
-
36Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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