A suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors

Rajiv S. Jumani, Muhammad M. Hasan, Erin E. Stebbins, Liam Donnelly, Peter Miller, Connor Klopfer, Kovi Bessoff, Jose E. Teixeira, Melissa S. Love, Case W. McNamara and Christopher D. Huston ()
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Rajiv S. Jumani: University of Vermont Larner College of Medicine
Muhammad M. Hasan: University of Vermont Larner College of Medicine
Erin E. Stebbins: University of Vermont Larner College of Medicine
Liam Donnelly: University of Vermont Larner College of Medicine
Peter Miller: University of Vermont Larner College of Medicine
Connor Klopfer: University of Vermont Larner College of Medicine
Kovi Bessoff: University of Vermont Larner College of Medicine
Jose E. Teixeira: University of Vermont Larner College of Medicine
Melissa S. Love: Calibr at The Scripps Research Institute
Case W. McNamara: Calibr at The Scripps Research Institute
Christopher D. Huston: University of Vermont Larner College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Cryptosporidiosis is a leading cause of life-threatening diarrhea in children, and the only currently approved drug is ineffective in malnourished children and immunocompromised people. Large-scale phenotypic screens are ongoing to identify anticryptosporidial compounds, but optimal approaches to prioritize inhibitors and establish a mechanistically diverse drug development pipeline are unknown. Here, we present a panel of medium-throughput mode of action assays that enable testing of compounds in several stages of the Cryptosporidium life cycle. Phenotypic profiles are given for thirty-nine anticryptosporidials. Using a clustering algorithm, the compounds sort by phenotypic profile into distinct groups of inhibitors that are either chemical analogs (i.e. same molecular mechanism of action (MMOA)) or known to have similar MMOA. Furthermore, compounds belonging to multiple phenotypic clusters are efficacious in a chronic mouse model of cryptosporidiosis. This suite of phenotypic assays should ensure a drug development pipeline with diverse MMOA without the need to identify underlying mechanisms.

Date: 2019
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DOI: 10.1038/s41467-019-09880-w

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