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

Nat Commun. 2019 Apr 23;10(1):1862. doi: 10.1038/s41467-019-09880-w.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Antiparasitic Agents / pharmacology*
  • Antiparasitic Agents / therapeutic use
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cluster Analysis
  • Cryptosporidiosis / drug therapy*
  • Cryptosporidiosis / parasitology
  • Cryptosporidium / drug effects*
  • Cryptosporidium / growth & development
  • Diarrhea / drug therapy*
  • Diarrhea / parasitology
  • Disease Models, Animal
  • Drug Discovery / methods
  • Growth Inhibitors / pharmacology*
  • Growth Inhibitors / therapeutic use
  • Humans
  • Life Cycle Stages / drug effects
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenotype

Substances

  • Antiparasitic Agents
  • Growth Inhibitors