Fidaxomicin

Clostridium difficile is a Gram-positive bacterium that causes various gastrointestinal complications, such as antibiotic-associated diarrhea. C. difficile infection can be caused by antibiotic therapy, resulting in the disruption of the human gut flora leads to an overgrowth of C. difficile. The consequences of C. difficile infection can be mild to severe and sometimes fatal.

Fidaxomicin gets hydrolyzed to its active metabolite, OP-1118, upon oral administration. Both compounds mediate a bactericidal activity against C. difficile by inhibiting bacterial RNA polymerase at the initiation phase of the transcription cycle. The RNA polymerase is an essential bacterial enzyme that regulates gene expression, catalyzes nucleic acid interactions, and promotes several bacterial enzymatic reactions critical for bacterial survival. The core RNA polymerase is composed of a complex of different subunits and contains the active site. To initiate bacterial transcription, the active site of the core RNA polymerase binds to a promoter-specificity σ initiation factor, which locates and binds to a promoter region of the DNA. The DNA-RNA polymerase interaction promotes subsequent steps of transcription, which involves the separation of DNA strands. Fidaxomicin binds to the DNA template-RNA polymerase complex, thereby preventing the initial separation of DNA strands during transcription and inhibiting messenger RNA synthesis. The narrow spectrum of antimicrobial activity of fidaxomicin may be explained by the unique target site of fidaxomicin and differing σ subunits of the core structure of RNA polymerase among bacterial species.