Format

Send to

Choose Destination
Antimicrob Agents Chemother. 2018 Mar 27;62(4). pii: e01505-17. doi: 10.1128/AAC.01505-17. Print 2018 Apr.

A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.

Author information

1
Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA.
2
Cellular, Molecular and Biomedical Sciences Graduate Program, University of Vermont, Burlington, Vermont, USA.
3
California Institute for Biomedical Research, La Jolla, California, USA.
4
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
5
Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
6
Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA christopher.huston@uvm.edu.

Abstract

Cryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies, in vitro toxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound against Cryptosporidium parvum Iowa and field isolates was comparable to that against Cryptosporidium hominis Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic for C. parvum, we developed a novel in vitro parasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stage Cryptosporidium drug leads and may aid in planning in vivo efficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

KEYWORDS:

AIDS; Cryptosporidium; cryptosporidiosis; diarrhea; piperazine

PMID:
29339392
PMCID:
PMC5913971
DOI:
10.1128/AAC.01505-17
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center