ArticleThe Journal of infectious diseases2016
Threading the Needle: Small-Molecule Targeting of a Xenobiotic Receptor to Ablate Escherichia coli Polysaccharide Capsule Expression Without Altering Antibiotic Resistance.
Article in The Journal of infectious diseases, 2016. 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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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria.The Journal of experimental medicine · 2022Article
- Regulation ofFrontiers in microbiology · 2022Review
- Article
- Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.Nucleic acids research · 2021Article
- Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies.Frontiers in microbiology · 2021Review
- Optimization of a Noncanonical Anti-infective: Interrogation of the Target Binding Pocket for a Small-Molecule Inhibitor of Escherichia coli Polysaccharide Capsule Expression.Antimicrobial agents and chemotherapy · 2020Article
- MarR family proteins are important regulators of clinically relevant antibiotic resistance.Protein science : a publication of the Protein Society · 2020Review
- Identification of Host Adaptation Genes in Extraintestinal Pathogenic Escherichia coli during Infection in Different Hosts.Infection and immunity · 2019Article
- Biosynthesis of a conserved glycolipid anchor for Gram-negative bacterial capsules.Nature chemical biology · 2019Article
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Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundUropathogenic Escherichia coli (UPEC), a leading cause of urinary tract and invasive infections worldwide, is rapidly acquiring multidrug resistance, hastening the need for selective new anti-infective agents. Here we demonstrate the molecular target of DU011, our previously discovered potent, nontoxic, small-molecule inhibitor of UPEC polysaccharide capsule biogenesis and virulence.
methodsReal-time polymerase chain reaction analysis and a target-overexpression drug-suppressor screen were used to localize the putative inhibitor target. A thermal shift assay quantified interactions between the target protein and the inhibitor, and a novel DNase protection assay measured chemical inhibition of protein-DNA interactions. Virulence of a regulatory target mutant was assessed in a murine sepsis model.
resultsMprA, a MarR family transcriptional repressor, was identified as the putative target of the DU011 inhibitor. Thermal shift measurements indicated the formation of a stable DU011-MprA complex, and DU011 abrogated MprA binding to its DNA promoter site. Knockout of mprA had effects similar to that of DU011 treatment of wild-type bacteria: a loss of encapsulation and complete attenuation in a murine sepsis model, without any negative change in antibiotic resistance.
conclusionsMprA regulates UPEC polysaccharide encapsulation, is essential for UPEC virulence, and can be targeted without inducing antibiotic resistance.
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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.