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Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.

ABSTRACT: Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes. Point mutations in TgCPSF3 introduced into wild-type parasites using the CRISPR/Cas9 system recapitulated the resistance phenotype. Importantly, mice infected with T. gondii and treated orally with AN3661 did not develop any apparent illness, while untreated controls had lethal infections. Therefore, TgCPSF3 is a promising novel target of T. gondii that provides an opportunity for the development of anti-parasitic drugs.

SUBMITTER: Palencia A

PROVIDER: S-EPMC5331205 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.

Palencia Andrés A Bougdour Alexandre A Brenier-Pinchart Marie-Pierre MP Touquet Bastien B Bertini Rose-Laurence RL Sensi Cristina C Gay Gabrielle G Vollaire Julien J Josserand Véronique V Easom Eric E Freund Yvonne R YR Pelloux Hervé H Rosenthal Philip J PJ Cusack Stephen S Hakimi Mohamed-Ali MA

EMBO molecular medicine 20170301 3

Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which ...[more]

PMID: 28148555

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Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.

Publications

Targeting <i>Toxoplasma gondii</i> CPSF3 as a new approach to control toxoplasmosis.

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