{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:26:26Z","timestamp":1791296786398,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2013,9,13]],"date-time":"2013-09-13T00:00:00Z","timestamp":1379030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T00:00:00Z","timestamp":1380585600000},"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":[[2013,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n The novel nitroimidazopyran agent (\n S<\/jats:italic>\n )-PA-824 has potent antibacterial activity against\n Mycobacterium tuberculosis<\/jats:named-content>\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n and is currently in phase II clinical trials for tuberculosis (TB). In contrast to\n M. tuberculosis<\/jats:named-content>\n , where (\n R<\/jats:italic>\n )-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against\n Leishmania donovani<\/jats:named-content>\n , the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (\n R<\/jats:italic>\n )-PA-824 is 6-fold more active than (\n S<\/jats:italic>\n )-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n pharmacological profiles of the two enantiomers are similar, (\n R<\/jats:italic>\n )-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight\n \u22121<\/jats:sup>\n , twice daily for 5 days. In\n M. tuberculosis<\/jats:named-content>\n , (\n S<\/jats:italic>\n )-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in\n Leishmania<\/jats:named-content>\n spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (\n R<\/jats:italic>\n )-PA-824 or (\n S<\/jats:italic>\n )-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies\n in vitro<\/jats:italic>\n indicate that fexinidazole and (\n R<\/jats:italic>\n )-PA-824 are additive whereas (\n S<\/jats:italic>\n )-PA-824 and (\n R<\/jats:italic>\n )-PA-824 show mild antagonistic behavior. Thus, (\n R<\/jats:italic>\n )-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.\n <\/jats:p>","DOI":"10.1128\/aac.00722-13","type":"journal-article","created":{"date-parts":[[2013,7,16]],"date-time":"2013-07-16T01:05:28Z","timestamp":1373936728000},"page":"4699-4706","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":69,"title":["The\n R<\/i>\n Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis"],"prefix":"10.1128","volume":"57","author":[{"given":"Stephen","family":"Patterson","sequence":"first","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Wyllie","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laste","family":"Stojanovski","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan R.","family":"Perry","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick R. 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