Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model
Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model
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DOI：
10.1016/j.ijantimicag.2017.08.020
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发表时间：
2018-01-01
影响因子：
10.8
通讯作者：
Govender, Thavendran
中科院分区：
文献类型：
--
作者：
Baijnath, Sooraj;Moodley, Chivonne;Govender, Thavendran
结核病（TB）几十年来一直是人类的祸害，夺去了无数人的生命。结核分枝杆菌能够感染肺外部位，特别是大脑，这使情况进一步复杂化。这些肺外形式的TB由于与药物递送穿过血脑屏障相关的问题而难以治疗。利奈唑胺（LIN）和氯法齐明（CFZ）是近年来两种较有前途的抗结核药物。本研究用M.结核病H37 Rv的小鼠，并用LIN [100 mg/kg体重（BW）]或CFZ（100 mg/kg BW）处理4周。同时，研究了气溶胶结核病感染是否会导致结核杆菌传播到大脑中。测定治疗后脑和肺CFU以及血清、肺和脑药物浓度。CFZ在肺中显示出强的杀菌作用，而LIN具有抑菌作用。结核分枝杆菌在感染后2周出现在未治疗组中（2.38 +/- 0.43 log 10 CFU），更令人惊讶的是在感染后3周出现在LIN治疗组中（1.14 +/- 0.99 log 10 CFU）。在CFZ治疗组的脑中未检测到结核杆菌。据我们所知，这是第一个研究显示的外观M。小鼠气溶胶结核感染后大脑中的结核病。这项研究可能会提倡使用CFZ作为预防性治疗，以预防中枢神经系统肺外结核的发展，使用双管齐下的方法。(c)2017 Elsevier B. V.和国际化疗学会。All rights reserved.
Tuberculosis (TB) has been the scourge of the human race for many decades, claiming countless number of lives. This is further complicated by the ability of Mycobacterium tuberculosis to infect extrapulmonary sites, specifically the brain. These extrapulmonary forms of TB are difficult to treat owing to problems associated with drug delivery across the blood-brain barrier. Linezolid (LIN) and clofazimine (CFZ) are two of the more promising anti-TB drugs in recent times. In this study, BALB/c mice were aerosol-infected with M. tuberculosis H37Rv and were treated for 4 weeks with LIN [100 mg/kg body weight (BW)] or CFZ (100 mg/kg BW). Concurrently, it was investigated whether an aerosol TB infection would lead to dissemination of TB bacilli into the brain. Post-treatment brain and lung CFUs were determined together with serum, lung and brain drug concentrations. CFZ displayed a strong bactericidal effect in the lung, whilst LIN had a bacteriostatic effect. Mycobacterium tuberculosis appeared at 2 weeks post-infection in the untreated group (2.38 +/- 0.43 log10 CFU) and more surprisingly at 3 weeks post-infection in the LIN-treated group (1.14 +/- 0.99 log10 CFU). TB bacilli could not be detected in the brains of the CFZ-treated group. To the best of our knowledge, this is the first study showing the appearance of M. tuberculosis in the brain following a murine aerosol TB infection. This study may advocate the use of CFZ as prophylactic treatment to prevent the development of extrapulmonary TB of the central nervous system using a two-pronged approach. (c) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.