title: Novel small molecule inhibitors targeting the "switch region" of bacterial RNAP: structure-based optimization of a virtual screening hit.
abstract: Rising resistance against current antibiotics necessitates the development of antibacterial agents with alternative targets. The "switch region" of RNA polymerase (RNAP), addressed by the myxopyronins, could be such a novel target site. Based on a hit candidate discovered by virtual screening, a small library of 5-phenyl-3-ureidothiophene-2-carboxylic acids was synthesized resulting in compounds with increased RNAP inhibition. Hansch analysis revealed π (lipophilicity constant) and σ (Hammet substituent constant) of the substituents at the 5-phenyl moiety to be crucial for activity. The binding mode was proven by the targeted introduction of a moiety mimicking the enecarbamate side chain of myxopyronin into the hit compound, accompanied by enhanced RNAP inhibitory potency. The new compounds displayed good antibacterial activities against Gram positive bacteria and Gram negative Escherichia coli TolC and a reduced resistance frequency compared to the established antibiotic rifampicin.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Drug Design and Optimization, Campus C2 3, 66123 Saarbrücken, Germany.
authors.forename: J Henning
authors.initials: JH
authors.lastname: Sahner
authors.forename: Matthias
authors.initials: M
authors.lastname: Groh
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Jörg
authors.initials: J
authors.lastname: Haupenthal
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C586278:5-phenyl-3-ureidothiophene-2-carboxylic acid; D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013876:Thiophenes; D012321:DNA-Directed RNA Polymerases
keywords: Antibacterial agent; Bacterial RNAP inhibitor; Myxopyronin; QSAR; Switch region; Ureidothiophene carboxylic acid