Characterization of anti-Toxoplasma activity of SDZ 215-918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl- isomerase-inhibiting activity: Possible role of a P glycoprotein in Toxoplasma physiology

Jared A. Silverman, Mary Lou Hayes, Benjamin J. Luft, Keith A Joiner

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38 Citations (Scopus)

Abstract

The immunosuppressive agent cyclosporin A (CsA) also possesses broad- spectrum antimicrobial activity. Previous investigators have reported that the obligate intracellular protozoan Toxoplasma gondii is sensitive to CsA. We have measured the sensitivity of Toxoplasma to 26 CSA derivatives that maintain only a subset of the parent compound s activity. We identified one compound, SDZ 215-918, that is a particularly potent inhibitor of parasite invasion and replication with a 50% inhibitory concentration of 0.45 μg/ml, which is 10-fold lower than that of CsA. Kinetic studies demonstrate that activity has a rapid onset(half-life, ≤20 min) and is initially reversible, although long-term exposure (>24 h) to 5 μg/ml is lethal; in contrast, this concentration had no effect on host cell protein synthesis or cell division. SDZ 215-918 acts directly on the parasite, as demonstrated by inhibition of macromolecular synthesis in host-free extracellular parasites. Inhibition of invasion is due to a reduction in parasite motility. SDZ 215-918 does not bind to cyclophilins, the ubiquitous cyclosporin-binding proteins, but is a potent inhibitor of the mammalian P glycoprotein, a member of the ATP binding cassette transporter superfamily and the pump responsible for multidrug resistance in cancer and parasite cell lines. SDZ 215-918 blocks the efflux of rhodamine 123 from extracellular parasites, consistent with inhibition of a P glycoprotein-like pump. We suggest that a P glycoprotein or a related transporter plays a crucial role in the biology of Toxoplasma and may be a novel target for antiparasitic compounds. Preliminary studies with animals indicate that SDZ 215-918 inhibits parasite growth in vivo; its relationship to CsA may make it suitable for clinical development.

Original languageEnglish (US)
Pages (from-to)1859-1866
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume41
Issue number9
StatePublished - Sep 1997
Externally publishedYes

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Peptidylprolyl Isomerase
Toxoplasma
P-Glycoprotein
Immunosuppressive Agents
Cyclosporine
Parasites
Cyclophilins
Rhodamine 123
Antiparasitic Agents
ATP-Binding Cassette Transporters
Multiple Drug Resistance
SDZ 215-918
Cell Division
Inhibitory Concentration 50
Half-Life
Research Personnel
Cell Line
Growth

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

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title = "Characterization of anti-Toxoplasma activity of SDZ 215-918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl- isomerase-inhibiting activity: Possible role of a P glycoprotein in Toxoplasma physiology",
abstract = "The immunosuppressive agent cyclosporin A (CsA) also possesses broad- spectrum antimicrobial activity. Previous investigators have reported that the obligate intracellular protozoan Toxoplasma gondii is sensitive to CsA. We have measured the sensitivity of Toxoplasma to 26 CSA derivatives that maintain only a subset of the parent compound s activity. We identified one compound, SDZ 215-918, that is a particularly potent inhibitor of parasite invasion and replication with a 50{\%} inhibitory concentration of 0.45 μg/ml, which is 10-fold lower than that of CsA. Kinetic studies demonstrate that activity has a rapid onset(half-life, ≤20 min) and is initially reversible, although long-term exposure (>24 h) to 5 μg/ml is lethal; in contrast, this concentration had no effect on host cell protein synthesis or cell division. SDZ 215-918 acts directly on the parasite, as demonstrated by inhibition of macromolecular synthesis in host-free extracellular parasites. Inhibition of invasion is due to a reduction in parasite motility. SDZ 215-918 does not bind to cyclophilins, the ubiquitous cyclosporin-binding proteins, but is a potent inhibitor of the mammalian P glycoprotein, a member of the ATP binding cassette transporter superfamily and the pump responsible for multidrug resistance in cancer and parasite cell lines. SDZ 215-918 blocks the efflux of rhodamine 123 from extracellular parasites, consistent with inhibition of a P glycoprotein-like pump. We suggest that a P glycoprotein or a related transporter plays a crucial role in the biology of Toxoplasma and may be a novel target for antiparasitic compounds. Preliminary studies with animals indicate that SDZ 215-918 inhibits parasite growth in vivo; its relationship to CsA may make it suitable for clinical development.",
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AU - Hayes, Mary Lou

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