ArticleMolecular microbiology2017
Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition.
Article in Molecular microbiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Article
- Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems.Frontiers in cellular and infection microbiology · 2022Review
- Developing Cyclic Peptomers as Broad-Spectrum Type III Secretion System Inhibitors in Gram-Negative Bacteria.Antimicrobial agents and chemotherapy · 2021Article
- Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components.Biomolecules · 2021Review
- Possible drugs for the treatment of bacterial infections in the future: anti-virulence drugs.The Journal of antibiotics · 2021Review
- On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome.MedChemComm · 2019Review
- Transcriptional responses of Xanthomonas oryzae pv. oryzae to type III secretion system inhibitor ortho-coumaric acid.BMC microbiology · 2019Article
- Control freaks-signals and cues governing the regulation of virulence in attaching and effacing pathogens.Biochemical Society transactions · 2019Review
- Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target.EcoSal Plus · 2019Review
- The Type III Secretion System (T3SS)-Translocon of Atypical EnteropathogenicFrontiers in microbiology · 2019Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gram-negative bacteria, including enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC. Affinity chromatography experiments identified the primary target of the compounds as the T3SS needle pore protein EspD, which is essential for effector protein translocation into host cells. These data were supported by mechanistic studies that determined the coiled-coil domain 1 of EspD as a key compound-binding site, thereby preventing correct assembly of the T3SS complex on the cell surface. However, binding of inhibitors to EspD or deletion of EspD itself did not result in transcriptional down-regulation of effector proteins. Instead, we found the compounds to exhibit dual-functionality by also down-regulating transcription of the entire chromosomal locus encoding the T3SS, further demonstrating their desirability and effectiveness.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.