Effect of the pseudomonas metabolites HQNO on the Toxoplasma gondii RH strain in vitro and in vivo

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance Pub Date : 2023-04-01 DOI:10.1016/j.ijpddr.2023.02.001

Jiao Mo , Hongfei Si , Siyang Liu , Qingyuan Zeng , Minghao Cai , Zhendi Liu , Jiyu Zhang , Jingjing Fang , Jili Zhang

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Abstract

Toxoplasmosis is a widespread disease in humans and animals. Currently, toxoplasmosis chemotherapy options are limited due to severe side effects. There is an urgent need to develop new drugs with better efficacy and few side effects. HQNO, a cytochrome bc1 and type II NADH inhibitor in eukaryotes and bacteria, possesses extensive bioactivity. In this study, the cytotoxicity of HQNO was evaluated in Vero cells. The in vitro effects of HQNO were determined by plaque assay and qPCR assay. To determine the in vivo effect of HQNO, pharmacokinetic experiments and in vivo infection assays were performed in mice. The changes in tachyzoites after HQNO exposure were examined by transmission electron microscopy (TEM), MitoTracker Red CMXRos staining, ROS detection and ATP detection. HQNO inhibited T. gondii invasion and proliferation with an EC₅₀ of 0.995 μM. Pharmacokinetic experiments showed that the C_max of HQNO (20 mg/kg·bw) was 3560 ± 1601 ng/mL (13.73 μM) in healthy BALB/c mouse plasma with no toxicity in vivo. Moreover, HQNO induced a significant decrease in the parasite burden load of T. gondii in mouse peritoneum. TEM revealed alterations in the mitochondria of T. gondii. Further assays verified that HQNO also decreased the mitochondrial membrane potential (ΔΨm) and ATP levels and enhanced the level of reactive oxygen species (ROS) in T. gondii. Hence, HQNO exerted anti-T. gondii activity, which may be related to the damage to the mitochondrial electron transport chain (ETC).

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假单胞菌代谢产物HQNO对弓形虫RH株的体内外影响

弓形虫病是一种广泛存在于人类和动物中的疾病。目前，弓形虫病化疗方案由于严重的副作用而受到限制。迫切需要开发出疗效更好、副作用少的新药。HQNO是真核生物和细菌中的细胞色素bc1和II型NADH抑制剂，具有广泛的生物活性。在本研究中，HQNO在Vero细胞中的细胞毒性进行了评估。通过菌斑法和qPCR法测定HQNO的体外作用。为了确定HQNO的体内作用，在小鼠中进行了药代动力学实验和体内感染测定。通过透射电子显微镜（TEM）、MitoTracker Red CMXRos染色、ROS检测和ATP检测检测HQNO暴露后速殖子的变化。HQNO对弓形虫的侵袭和增殖具有抑制作用，EC50为0.995μM。药代动力学实验表明，HQNO（20mg/kg·bw）在健康BALB/c小鼠血浆中的Cmax为3560±1601ng/mL（13.73μM），在体内无毒性。此外，HQNO诱导小鼠腹膜中弓形虫的寄生虫负荷显著降低。透射电镜显示弓形虫线粒体发生改变。进一步的分析证实，HQNO还降低了弓形虫的线粒体膜电位（ΔΨm）和ATP水平，并提高了活性氧（ROS）的水平。因此HQNO可发挥抗T的作用。弓形虫活性，这可能与线粒体电子传递链（ETC）的损伤有关。

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来源期刊

International Journal for Parasitology: Drugs and Drug Resistance PARASITOLOGY-PHARMACOLOGY & PHARMACY

CiteScore

7.90

自引率

7.50%

发文量

审稿时长

48 days

期刊介绍： The International Journal for Parasitology – Drugs and Drug Resistance is one of a series of specialist, open access journals launched by the International Journal for Parasitology. It publishes the results of original research in the area of anti-parasite drug identification, development and evaluation, and parasite drug resistance. The journal also covers research into natural products as anti-parasitic agents, and bioactive parasite products. Studies can be aimed at unicellular or multicellular parasites of human or veterinary importance.