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Currently, available treatment is limited, and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptosporidium<\/jats:named-content>drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for<jats:italic>in vivo<\/jats:italic>efficacy have not been established. We have been engaged in a<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptosporidium<\/jats:named-content>drug discovery program targeting IMP dehydrogenase (<jats:italic>Cp<\/jats:italic>IMPDH). Here, we report the activity of eight potent and selective inhibitors of<jats:italic>Cp<\/jats:italic>IMPDH in the interleukin-12 (IL-12) knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating<jats:italic>Cp<\/jats:italic>IMPDH as a drug target. The best compound, P131 (250 mg\/kg of body weight\/day), performed equivalently to paromomycin (2,000 mg\/kg\/day) when administered in a single dose and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Cryptosporidium<\/jats:named-content>infection. The pharmacokinetic, uptake, and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for<jats:italic>in vivo<\/jats:italic>antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.<\/jats:p>","DOI":"10.1128\/aac.02075-13","type":"journal-article","created":{"date-parts":[[2013,12,24]],"date-time":"2013-12-24T04:23:33Z","timestamp":1387859013000},"page":"1603-1614","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":71,"title":["Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis"],"prefix":"10.1128","volume":"58","author":[{"given":"Suresh Kumar","family":"Gorla","sequence":"first","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina N.","family":"McNair","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center and Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatakrishna R.","family":"Jala","sequence":"additional","affiliation":[{"name":"James Graham Brown Cancer Center and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodduluri","family":"Haribabu","sequence":"additional","affiliation":[{"name":"James Graham Brown Cancer Center and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Striepen","sequence":"additional","affiliation":[{"name":"Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Cuny","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA"},{"name":"Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan R.","family":"Mead","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center and Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizbeth","family":"Hedstrom","sequence":"additional","affiliation":[{"name":"Department of Biology, Brandeis University, Waltham, Massachusetts, USA"},{"name":"Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2009.02.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4103\/2229-5070.105173"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e328357e569"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/503189a"},{"key":"e_1_3_3_6_2","first-page":"1","article-title":"Surveillance for waterborne disease outbreaks and other health events associated with recreational water\u2014United States, 2007\u20132008","volume":"60","author":"Hlavsa MC","year":"2011","unstructured":"HlavsaMCRobertsVAAndersonARHillVRKahlerAMOrrMGarrisonLEHicksLANewtonAHilbornEDWadeTJBeachMJYoderJS. 2011. 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