2012
DOI: 10.1128/jb.01103-12
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Novel Rapidly Diversifiable Antimicrobial RNA Polymerase Switch Region Inhibitors with Confirmed Mode of Action in Haemophilus influenzae

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… Show more

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Cited by 27 publications
(34 citation statements)
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“…E. coli MRE600 cells were used to prepare wild-type S30 cell extract, as described previously (37). Mutant E. coli S30 cell extract was prepared as wild-type extract but using an E. coli strain bearing a U1782C U2586C double mutant.…”
Section: Methodsmentioning
confidence: 99%
“…E. coli MRE600 cells were used to prepare wild-type S30 cell extract, as described previously (37). Mutant E. coli S30 cell extract was prepared as wild-type extract but using an E. coli strain bearing a U1782C U2586C double mutant.…”
Section: Methodsmentioning
confidence: 99%
“…More recently, synthetic scaffolds including ureidothiophene-2-carboxylic acid-based inhibitors 21, 26 , and squaramide-based inhibitors (Fig. 1B) 27 have been added. Structural and biochemical studies of Myx-mediated inhibition of RNAP culminated into two possible hypotheses regarding its mechanism.…”
Section: Introductionmentioning
confidence: 99%
“…Strains exist with efflux pumps knocked out either individually or in combination, and the relative contribution of each system to the susceptibility to major classes of antimicrobials has been defined (15). For the most part, tolC is the major contributor to efflux in E. coli, and knockout of this gene is often used to assess whether novel compounds lack cellular activity due to efflux (16)(17)(18)(19)(20)(21)(22)(23)(24). Similarly, mutations in several genesincluding lpxC (25-27), lptD (28, 29), and lptE (30, 31)-leading to increased permeability of E. coli have been described, and strains harboring such lesions are often used to assess the effect of increased cellular penetration on the bioactivity of molecules (32-37).…”
mentioning
confidence: 99%