Repositioning Candidate Details
| Candidate ID: | R1173 |
| Source ID: | DB08874 |
| Source Type: | approved |
| Compound Type: | small molecule |
| Compound Name: | Fidaxomicin |
| Synonyms: | Difimicin ; Fidaxomicin; Lipiarmicin; Lipiarmycin; Lipiarrmycin; Tiacumicin B |
| Molecular Formula: | C52H74Cl2O18 |
| SMILES: | [H][C@@]1(O[C@@H]2[C@@H](CC)\C=C(C)\[C@@H](O)C\C=C\C=C(CO[C@@H]3O[C@H](C)[C@@H](OC(=O)C4=C(CC)C(Cl)=C(O)C(Cl)=C4O)[C@H](O)[C@@H]3OC)\C(=O)O[C@@H](C\C=C(/C)\C=C2/C)[C@@H](C)O)OC(C)(C)[C@@H](OC(=O)C(C)C)[C@H](O)[C@@H]1O |
| Structure: |
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| DrugBank Description: | Fidaxomicin is a novel macrolide antibiotic used in the treatment of diarrhea caused by _Clostridioides_ (formerly _Clostridium_) _difficile_ in adult and pediatric patients over the age of 6 months. Fidaxomicin is a naturally-occurring 18-member macrocycle derived from fermentation. Because fidaxomicin contains an 18-membered lactone ring in its structure, it is referred to as a macrocyclic lactone antibiotic drug. The antibacterial activity of fidaxomicin is distinct from macrolides and rifamycins, as the bactericidal activity is time-dependent, and not concentration-dependent. Fidaxomicin was the first macrocyclic lactone antibiotic with activity against _C. difficile_, and it displays a narrow spectrum of activity against gram-positive anaerobes. It mediates its potent bactericidal action on the bacteria by inhibiting the bacterial RNA synthase, thereby disrupting bacterial transcription. The minimum inhibitory concentration (MIC<sub>90</sub>) for fidaxomicin is four times less than that of , which was the primary drug of choice for _C. difficile_ infection before the approval of fidaxomicin. Unlike vancomycin, however, fidaxomicin has a negligible effect on normal colonic microflora. The FDA initially approved fidaxomicin in May 2011 for the treatment of _C. difficile_-associated diarrhea in adult patients over the age of 18. Later that year in December, the drug was also approved by the European Medicine Agency. In June 2012, fidaxomicin was also granted approval by Health Canada. The approved indication of fidaxomicin was expanded by the FDA in January 2020 to include pediatric patients over the age of 6 months in the treatment population. |
| CAS Number: | 873857-62-6 |
| Molecular Weight: | 1058.05 |
| DrugBank Indication: | Fidaxomicin is indicated for the treatment of _Clostridioides_ (formerly _Clostridium_) _difficile_-associated diarrhea in adult and pediatric patients 6 months of age and older. Fidaxomicin should only be used in patients with proven or strongly suspected _C. difficile_ infection to reduce the risk of development of drug-resistant bacteria and maximize the therapeutic effectiveness of fidaxomicin and other antimicrobial agents. |
| DrugBank Pharmacology: | Fidaxomicin has a narrow-spectrum antibacterial profile, with potent bactericidal activity specifically against C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against _C. difficile_ ranged from 0.0078 to 2 μg/mL _in vitro_. The bactericidal activity of fidaxomicin is time-dependent. Other than _C. difficile_, fidaxomicin has moderate inhibitory activity against Gram-positive bacteria (_S. aureus_ and _Enterococcus spp._) and poor activity against normal colonic flora, including anaerobes and enteric Gram-negative bacilli. Isolates of _C. difficile_ that are resistant to rifamycins or other antimicrobial classes (such as cephalosporins, fluoroquinolones, clindamycin) were not shown to be cross-resistant to fidaxomicin. |
| DrugBank MoA: | _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. |
| Targets: | RNA polymerase sigma factor inhibitor |
| Inclusion Criteria: | Therapeutic strategy associated |
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