Bedaquiline kills persistent Mycobacterium tuberculosis with no disease relapse: an in vivo model of a potential cure
Bedaquiline kills persistent Mycobacterium tuberculosis with no disease relapse: an in vivo model of a potential cure
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DOI：
10.1093/jac/dkz052
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发表时间：
2019-06-01
影响因子：
5.2
通讯作者：
Coates, Anthony
中科院分区：
文献类型：
--
作者：
Hu, Yanmin;Pertinez, Henry;Coates, Anthony
目的：非复制型持久性结核分枝杆菌很难杀死，因为使用我们的常规诊断方法无法检测到这种生物体，并且对抗结核药物具有耐受性。复苏促进因子（RPF）已被用来“唤醒”非复制的坚持者，使它们易于检测。贝达喹啉是一种新型的杀菌和消毒抗结核药物，具有根除RPF依赖的持久性M。结核我们首次对标准抗结核方案和贝达喹啉改良方案根除依赖RPF的持续性M。结核病，使用定义明确的康奈尔模型。用标准方案（利福平、异烟肼、吡嗪酰胺和乙胺丁醇）或用贝达喹啉代替乙胺丁醇的相同方案治疗结核病感染的小鼠14周。两种药物方案的疗效通过cfu计数消除和持久性细菌的根除来测量，使用含有RPF的培养滤液（CF）来评价。在治疗结束时，剩余的cfu计数阴性小鼠给予氢化可的松8周。诱导的疾病复发率由M阳性小鼠的百分比确定。结果：含贝达喹啉的方案在治疗开始后8周达到总器官cfu计数清除，比标准方案（14周）更快。重要的是，含有贝达喹啉的方案删除CF依赖的持久性bacilli在8周，导致没有疾病reactivity.Conclusions：贝达喹啉方案根除持续性结核病感染，并完全防止疾病复发的小鼠。这些发现为更快治愈结核病提供了可能，降低了复发率。
Objectives: Non-replicating persistent Mycobacterium tuberculosis is difficult to kill since the organisms become undetectable using our conventional diagnostic methods and tolerant to anti-TB drugs. Resuscitation-promoting factors (RPFs) have been used to 'wake up' non-replicating persisters, making them easy to detect. Bedaquiline is a novel bactericidal and sterilizing anti-TB drug with the potential to eradicate RPF-dependent persistent M. tuberculosis. We present the first head-to-head comparison between the standard anti-TB regimen and a bedaquiline-modified regimen in eradicating RPF-dependent persistent M. tuberculosis, using the well-defined Cornell Model.Methods: M. tuberculosis-infected mice were treated for 14 weeks with either the standard regimen (rifampicin, isoniazid, pyrazinamide and ethambutol) or the same regimen where ethambutol was replaced by bedaquiline. The efficacy of both drug regimens was measured by cfu count elimination and eradication of persistent bacteria, which was evaluated using culture filtrate (CF) containing RPFs. At the end of treatment, the remaining cfu count-negative mice were administered hydrocortisone for 8 weeks. The induced disease relapse rates were determined by the percentage of mice that became positive for M. tuberculosis in the lung, spleen or both.Results: The bedaquiline-containing regimen achieved total organ cfu count clearance at 8 weeks after treatment initiation, faster than the standard regimen (14 weeks). Importantly, the bedaquiline-containing regimen removed CF-dependent persistent bacilli at 8 weeks, leading to no disease relapse.Conclusions: A bedaquiline regimen eradicated persistent TB infections and completely prevented disease relapse in mice. These findings offer the potential for a faster cure for TB, with reduced relapse rate.