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Experimental Therapeutics

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
J. Stone Doggett
aDivision of Infectious Diseases, Oregon Health and Science University School of Medicine, Portland, Oregon, USA
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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Tracey Schultz
cDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Alyssa J. Miller
dProgram in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
eDepartment of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Igor Bruzual
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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  • ORCID record for Igor Bruzual
Sovitj Pou
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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Rolf Winter
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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Rozalia Dodean
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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Lev N. Zakharov
fDepartment of Chemistry, University of Oregon, Eugene, Oregon, USA
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Aaron Nilsen
aDivision of Infectious Diseases, Oregon Health and Science University School of Medicine, Portland, Oregon, USA
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Michael K. Riscoe
aDivision of Infectious Diseases, Oregon Health and Science University School of Medicine, Portland, Oregon, USA
bDepartment of Hospital and Specialty Medicine, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
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Vern B. Carruthers
cDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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DOI: 10.1128/AAC.00535-20
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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.

FOOTNOTES

    • Received 19 March 2020.
    • Returned for modification 30 April 2020.
    • Accepted 3 June 2020.
    • Accepted manuscript posted online 15 June 2020.
  • For a companion article on this topic, see https://doi.org/10.1128/AAC.00539-20.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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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
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00535-20; DOI: 10.1128/AAC.00535-20

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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
Antimicrobial Agents and Chemotherapy Aug 2020, 64 (9) e00535-20; DOI: 10.1128/AAC.00535-20
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KEYWORDS

Toxoplasma gondii
animal models
cytochromes
drug discovery
Electron Transport
experimental therapeutics

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