普托马尼对利福平依赖结核菌感染小鼠的作用及其机制研究

Effect of pretomanid on rifampicin-dependent Mycobacterium tuberculosis infection in mice and its mechanism

摘要:

目的 探究普托马尼（PA-824）对利福平（RFP）依赖结核菌感染小鼠的作用及其机制研究。方法 将32只SD雄性小鼠随机分为RFP治疗组、PA-824治疗组、联合治疗组和对照组，每组8只。所有小鼠以结核分枝杆菌RFP依赖株攻毒，复制RFP依赖结核病小鼠模型，RFP治疗组给予65 mg/（kg·d）RFP，PA-824治疗组给予25 mg/（kg·d）PA-824，联合治疗组给予上述2种药物，对照组予以等量生理盐水灌胃。治疗6周后观察小鼠脾、肺组织重量，脏器致病指数，脾、肺组织荷菌量及肺组织病理学变化。结果 与对照组比较，RFP治疗组的肺重量、脾重量、脾菌量、肺菌量均升高（P <0.05），PA-824治疗组和联合治疗组的肺重量、脾重量、脏器致病指数评分、脾菌量、肺菌量均降低（P <0.05）；与联合治疗组比较，RFP治疗组和PA-824治疗组的肺重量、脾重量、脏器致病指数评分、脾菌量、肺菌量均升高（P <0.05）；与RFP治疗组比较，PA-824治疗组的肺重量、脾重量、脏器致病指数评分、脾菌量、肺菌量均降低（P <0.05）。结论 PA-824在抑制MTB对RFP依赖性的同时，对RFP依赖结核菌感染小鼠具有较好的抑制作用，同时对改善病变范围与病变程度均有一定的效果。

Abstract:

Objective To explore the effect of pretomanid (PA-824) on rifampicin (RFP)-dependent Mycobacterium tuberculosis infection in mice and its mechanism.Methods Thirty-two male SD mice were randomly divided into RFP treatment group, PA-824 treatment group, combination treatment group and control group, with 8 mice in each group. All mice were challenged with RFP-dependent strains of Mycobacterium tuberculosis to establish an RFP-dependent tuberculosis mouse model. The RFP treatment group was given 65 mg/(kg·d) of RFP, the PA-824 treatment group was given 25 mg/(kg·d) of PA-824, and the combination treatment group was given both the drugs in the above doses. The mice in the control group were given the same amount of normal saline by gavage. After 6 weeks of treatment, the weights of lung and spleen tissues, the organ severity score, the bacterial load of the lung and spleen tissues and the pathological results of lung tissues were observed.Results Compared with the control group, the weights and the bacterial load of lung and spleen were all higher in the RFP treatment group, while the weights of lung and spleen, the organ severity score, and the bacterial load of the lung and spleen in the PA-824 treatment group and the combination treatment group were lower (P < 0.05). Compared with the combination treatment group, the weights of lung and spleen, the organ severity score, and the bacterial load of the lung and spleen in the RFP treatment group and the PA-824 treatment group were increased (P < 0.05). Compared with the RFP treatment group, the weights of lung and spleen, the organ severity score, and the bacterial load of the lung and spleen in the PA-824 treatment group were decreased (P < 0.05).Conclusions PA-824 not only mitigates the RFP dependence for controlling Mycobacterium tuberculosis, but itself also exhibits a great inhibitory effect on RFP-dependent Mycobacterium tuberculosis infection in mice. Meanwhile, it may reduce the extent and severity of the lesions in some way.