Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis

• Authors: Suresh Kumar Gorla, Brandeis University; Nina N. McNair, Emory University; Guangyi Yang, University of Houston; Song Gao, University of Houston; Ming Hu, University of Houston; Venkatakrishna R. Jala, University of Louisville; Bodduluri Haribabu, University of Louisville; Boris Striepen, University of Georgia; Gregory D. Cuny, University of Houston; Jan Mead, Emory University; Lizbeth Hedstrom, Brandeis University
• Journal Title: Antimicrobial Agents and Chemotherapy
• Volume: Volume 58, Number 3
• Publisher: American Society for Microbiology | 2014-03-01, Pages 1603-1614
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1128/AAC.02075-13
• Subjects: Biology, Microbiology; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Microbiology; Pharmacology & Pharmacy; MICROBIOLOGY; PHARMACOLOGY & PHARMACY; INOSINE 5'-MONOPHOSPHATE DEHYDROGENASE; PARVUM INFECTION; IN-VITRO; IMMUNOSUPPRESSED RATS; DISCONTINUOUS SUCROSE; ORAL BIOAVAILABILITY; DEVELOPING-COUNTRIES; GENE-TRANSFER; CELL-CULTURE; BALB/C MICE

Abstract

Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world, and a potential bioterrorism agent. Currently, available treatment is limited, and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting IMP dehydrogenase (CpIMPDH). Here, we report the activity of eight potent and selective inhibitors of CpIMPDH in the interleukin-12 (IL-12) knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH 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 Cryptosporidium 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 in vivo 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.