{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T08:50:38Z","timestamp":1788684638535,"version":"build-2803163510"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2012,8,1]],"date-time":"2012-08-01T00:00:00Z","timestamp":1343779200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Clostridium difficile<\/jats:named-content>\n            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,\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Helicobacter pylori<\/jats:named-content>\n            , and\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Campylobacter jejuni<\/jats:named-content>\n            , also shows clinical efficacy against CDI. From a library of \u223c250 analogues of NTZ, we identified leads with increased potency for PFOR. MIC screens indicated\n            <jats:italic>in vitro<\/jats:italic>\n            activity in the 0.05- to 2-\u03bcg\/ml range against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. difficile<\/jats:named-content>\n            . 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\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. difficile<\/jats:named-content>\n            , 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.\n          <\/jats:p>","DOI":"10.1128\/aac.00360-12","type":"journal-article","created":{"date-parts":[[2012,5,15]],"date-time":"2012-05-15T05:40:21Z","timestamp":1337060421000},"page":"4103-4111","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Amixicile, a Novel Inhibitor of Pyruvate:Ferredoxin Oxidoreductase, Shows Efficacy against Clostridium difficile in a Mouse Infection Model"],"prefix":"10.1128","volume":"56","author":[{"given":"Cirle A.","family":"Warren","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and International Health, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA"},{"name":"Center for Global Health, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"van Opstal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and International Health, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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