Orally bioavailable endochin-like quinolone carbonate ester prodrug reduces toxoplasma gondii brain cysts

J. Stone Doggett, Tracey Schultz, Alyssa J. Miller, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia Dodean, Lev N. Zakharov, Aaron Nilsen, Michael K. Riscoe, Vern B. Carruthers

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for T. gondii cytochrome b over human cytochrome b. Despite its oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations, and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a 6-fold increase in both the maximum plasma concentration (Cmax) and the area under the curve (AUC) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in efficacy against acute toxoplasmosis greater than that of an equivalent dose of ELQ-316 and had efficacy against latent toxoplasmosis similar to that of ELQ-316 administered intraperitoneally. Treatment with carbonate ester prodrugs is a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.

Original languageEnglish (US)
Article numbere00535-20
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number9
DOIs
StatePublished - Sep 2020

Keywords

  • Animal models
  • Cytochromes
  • Drug discovery
  • Electron transport
  • Experimental therapeutics
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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