ArticleJournal of bacteriology2012
Novel rapidly diversifiable antimicrobial RNA polymerase switch region inhibitors with confirmed mode of action in Haemophilus influenzae.
Article in Journal of bacteriology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed, 29 citations in OpenAlex.
- High-throughput screening to discover inhibitors of the CarD·RNA polymerase protein-protein interaction in Mycobacterium tuberculosis.Scientific reports · 2020Article
- [New inhibitors targeting bacterial RNA polymerase].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2019Review
- Orientia tsutsugamushi Is Highly Susceptible to the RNA Polymerase Switch Region Inhibitor Corallopyronin AAntimicrobial agents and chemotherapy · 2018Article
- Bacterial Transcription as a Target for Antibacterial Drug Development.Microbiology and molecular biology reviews : MMBR · 2016Review
- Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics.Antimicrobial agents and chemotherapy · 2016Article
- Bacterial RNA Polymerase-DNA Interaction-The Driving Force of Gene Expression and the Target for Drug Action.Frontiers in molecular biosciences · 2016Review
- Structural Insights Lead to a Negamycin Analogue with Improved Antimicrobial Activity against Gram-Negative Pathogens.ACS medicinal chemistry letters · 2015Article
- Structural biology of bacterial RNA polymerase.Biomolecules · 2015Review
- X-ray crystal structures of Escherichia coli RNA polymerase with switch region binding inhibitors enable rational design of squaramides with an improved fraction unbound to human plasma protein.Journal of medicinal chemistry · 2015Article
- Synergy of streptogramin antibiotics occurs independently of their effects on translation.Antimicrobial agents and chemotherapy · 2014Article
- The role of a novel auxiliary pocket in bacterial phenylalanyl-tRNA synthetase druggability.The Journal of biological chemistry · 2014Article
- New insights into the bacterial RNA polymerase inhibitor CBR703 as a starting point for optimization as an anti-infective agent.Antimicrobial agents and chemotherapy · 2014Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A series of inhibitors with a squaramide core was synthesized following its discovery in a high-throughput screen for novel inhibitors of a transcription-coupled translation assay using Escherichia coli S30 extracts. The inhibitors were inactive when the plasmid substrate was replaced with mRNA, suggesting they interfered with transcription. This was confirmed by their inhibition of purified E. coli RNA polymerase. The series had antimicrobial activity against efflux-negative strains of E. coli and Haemophilus influenzae. Like rifampin, the squaramides preferentially inhibited synthesis of RNA and protein over fatty acids, peptidoglycan, and DNA. However, squaramide-resistant mutants were not cross-resistant to rifampin. Nine different mutations were found in parts of rpoB or rpoC that together encode the so-called switch region of RNA polymerase. This is the binding site of the natural antibiotics myxopyronin, corallopyronin, and ripostatin and the drug fidaxomicin. Computational modeling using the X-ray crystal structure of the myxopyronin-bound RNA polymerase of Thermus thermophilus suggests a binding mode of these inhibitors that is consistent with the resistance mutations. The squaramides are the first reported non-natural-product-related, rapidly diversifiable antibacterial inhibitors acting via the switch region of RNA polymerase.
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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.