title: Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis.
abstract: Fidaxomicin was recently approved for the treatment of Clostridium difficile infection. It inhibits transcription by bacterial RNA polymerase. Because transcription is a multistep process, experiments were conducted in which fidaxomicin was added at different stages of transcriptional initiation to identify the blocked step. DNA footprinting experiments were also conducted to further elucidate the stage inhibited. Fidaxomicin blocks initiation only if added before the formation of the "open promoter complex," in which the template DNA strands have separated but RNA synthesis has not yet begun. Binding of fidaxomicin precludes the initial separation of DNA strands that is prerequisite to RNA synthesis. These studies show that it has a mechanism distinct from that of elongation inhibitors, such as streptolydigin, and from the transcription initiation inhibitors myxopyronin and the rifamycins.
authors: Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA. artsimovitch.1@osu.edu
authors: Irina
authors: I
authors: Artsimovitch
authors: Jaime
authors: J
authors: Seddon
authors: Pamela
authors: P
authors: Sears
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D016360:Clostridioides difficile / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D018983:DNA Footprinting / Q000379:methods; D004269:DNA, Bacterial / Q000235:genetics; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D000077732:Fidaxomicin; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012329:RNA, Bacterial / Q000096:biosynthesis* / Q000235:genetics; D013379:Substrate Specificity; D014158:Transcription, Genetic
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D019384:Nucleic Acid Synthesis Inhibitors; D012329:RNA, Bacterial; D012321:DNA-Directed RNA Polymerases; D000077732:Fidaxomicin