High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth

Gregory D. Bowden, Kirkwood M. Land, Roberta M. O'Connor, Heather Fritz

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95% CI] or 21.9 ng/ml [12.1–40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection.

Original languageEnglish (US)
Pages (from-to)137-144
Number of pages8
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume8
Issue number1
DOIs
StatePublished - Apr 1 2018

Fingerprint

Drug Repositioning
Sarcocystis
Horses
Libraries
Encephalomyelitis
Growth
Parasites
Dantrolene
Dopamine Receptors
Nervous System Diseases

Keywords

  • Drug repurposing
  • Equine protozoal myeloencephalitis
  • High-throughput screen
  • Sarcocystis neurona

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth. / Bowden, Gregory D.; Land, Kirkwood M.; O'Connor, Roberta M.; Fritz, Heather.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 8, No. 1, 01.04.2018, p. 137-144.

Research output: Contribution to journalArticle

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abstract = "The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50{\%} of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70{\%} effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83{\%}) have activity against one or more related apicomplexans. Interestingly, nearly half (44{\%}; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95{\%} CI] or 21.9 ng/ml [12.1–40.3; 95{\%} CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection.",
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