Introduction: Toxoplasmosis is a major health issue worldwide, especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-Toxoplasma gondii activity. Methods: This study tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. Results: Among the most active compounds, an HDAC inhibitor showing an IC50 of 30 nM with a selectivity index above 100 was identified. MC1742 was active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induced hyper-acetylation of histones, while the acetylated tubulin level remained unchanged. After MC1742 treatment, the parasite expression profile was profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed in the tachyzoite stage. Conclusions: These findings suggest that this compound disturbs the Toxoplasma gondii gene expression program, inducing parasite death.

A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression / Mouveaux, T.; Rotili, D.; Boissavy, T.; Roger, E.; Pierrot, C.; Mai, A.; Gissot, M.. - In: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS. - ISSN 0924-8579. - 59:3(2022), p. 106526. [10.1016/j.ijantimicag.2022.106526]

A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression

Rotili D.;Mai A.;
2022

Abstract

Introduction: Toxoplasmosis is a major health issue worldwide, especially for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii. Although the drugs commonly used to treat toxoplasmosis are efficient, they present serious side effects and adverse events are common. Therefore, there is a need for the discovery of new compounds with potent anti-Toxoplasma gondii activity. Methods: This study tested compounds designed to target enzymes that are involved in the epigenetic regulation of gene expression. Results: Among the most active compounds, an HDAC inhibitor showing an IC50 of 30 nM with a selectivity index above 100 was identified. MC1742 was active at inhibiting the growth of the parasite in vitro but also at preventing the consequences of the acute disease in vivo. This compound induced hyper-acetylation of histones, while the acetylated tubulin level remained unchanged. After MC1742 treatment, the parasite expression profile was profoundly changed with the activation of genes preferentially expressed in the sexual stages that are normally repressed in the tachyzoite stage. Conclusions: These findings suggest that this compound disturbs the Toxoplasma gondii gene expression program, inducing parasite death.
HDAC; HDAC inhibitors; Malaria; Plasmodium; Toxoplasma; Toxoplasmosis; Animals; Epigenesis, Genetic; Gene Expression; Histone Deacetylase Inhibitors; Humans; Parasites; Toxoplasma
01 Pubblicazione su rivista::01a Articolo in rivista
A potent HDAC inhibitor blocks Toxoplasma gondii tachyzoite growth and profoundly disrupts parasite gene expression / Mouveaux, T.; Rotili, D.; Boissavy, T.; Roger, E.; Pierrot, C.; Mai, A.; Gissot, M.. - In: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS. - ISSN 0924-8579. - 59:3(2022), p. 106526. [10.1016/j.ijantimicag.2022.106526]
File allegati a questo prodotto
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1622839
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 6
social impact