Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model.

Abstract

Clostridium difficile infection (CDI) is a serious diarrheal disease that often develops following prior antibiotic usage. One of the major problems with current therapies (oral vancomycin and metronidazole) is the high rate of recurrence. Nitazoxanide (NTZ), an inhibitor of pyruvate:ferredoxin oxidoreductase (PFOR) in anaerobic bacteria, parasites, Helicobacter pylori, and Campylobacter jejuni, also shows clinical efficacy against CDI. From a library of ∼250 analogues of NTZ, we identified leads with increased potency for PFOR. MIC screens indicated in vitro activity in the 0.05- to 2-μg/ml range against C. difficile. To improve solubility, we replaced the 2-acetoxy group with propylamine, producing amixicile, a soluble (10 mg/ml), nontoxic (cell-based assay) lead that produced no adverse effects in mice by oral or intraperitoneal (i.p.) routes at 200 mg/kg of body weight/day. In initial efficacy testing in mice treated (20 mg/kg/day, 5 days each) 1 day after receiving a lethal inoculum of C. difficile, amixicile showed slightly less protection than did vancomycin by day 5. However, in an optimized CDI model, amixicile showed equivalence to vancomycin and fidaxomicin at day 5 and there was significantly greater survival produced by amixicile than by the other drugs on day 12. All three drugs were comparable by measures of weight loss/gain and severity of disease. Recurrence of CDI was common for mice treated with vancomycin or fidaxomicin but not for mice receiving amixicile or NTZ. These results suggest that gut repopulation with beneficial (non-PFOR) bacteria, considered essential for protection against CDI, rebounds much sooner with amixicile therapy than with vancomycin or fidaxomicin. If the mouse model is indeed predictive of human CDI disease, then amixicile, a novel PFOR inhibitor, appears to be a very promising new candidate for treatment of CDI.

• Authors: Cirle A Warren, Edward van Opstal, T Eric Ballard, Andrew Kennedy, Xia Wang, Mary Riggins, Igor Olekhnovich, Michelle Warthan, Glynis L Kolling, Richard L Guerrant, Timothy L Macdonald, Paul S Hoffman
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 8 Pg. 4103-11 (Aug 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22585229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aminoglycosides
• Anti-Bacterial Agents
• Benzamides
• Enzyme Inhibitors
• Nitro Compounds
• Thiazoles
• amixicile
• Vancomycin
• Pyruvate Synthase
• nitazoxanide
• Fidaxomicin

Topics

• Aminoglycosides (pharmacology)
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Clostridioides difficile (drug effects, enzymology)
• Clostridium Infections (drug therapy, microbiology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Fidaxomicin
• Mice
• Microbial Sensitivity Tests
• Nitro Compounds
• Pyruvate Synthase (antagonists & inhibitors)
• Thiazoles (chemistry, pharmacology, therapeutic use)
• Treatment Outcome
• Vancomycin (pharmacology)