One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics.
One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics.
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一种尺寸适合所有人？
DOI：
10.3389/fcimb.2021.613149
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发表时间：
2021
影响因子：
5.7
通讯作者：
Via LE
中科院分区：
文献类型：
--
作者：
Yang HJ;Wang D;Wen X;Weiner DM;Via LE
尽管几乎普遍努力为患者提供高效化疗，但结核病（TB）仍然是全球健康问题，部分原因是许多感染个体未被诊断和治疗，其他人未完成治疗，并且一小部分携带结核分枝杆菌（Mtb）菌株，其已对标准方案中的药物产生耐药性。在过去的10年中，结核病新药的开发和批准加速了，但由于结核分枝杆菌耐药性的发展以及将治疗时间缩短到4个月或更短的愿望，需要更多的药物。药物开发过程需要预测性动物模型，以概括人类疾病的复杂病理学和细菌负荷分布。人类宿主对Mtb肺部感染的反应是肉芽肿性炎症，通常导致包含的病变和有限的细菌复制。在那些发展为进行性或活动性疾病的人中，坏死和空洞区域可能发展导致持久的肺损伤和可能的死亡。本文介绍了主要的脊椎动物模型，用于评估化合物对结核分枝杆菌和疾病的介绍，发展活动。包括斑马鱼、各种小鼠、豚鼠、兔和非人灵长类动物在内的每种模型都提供了关于结核分枝杆菌细菌数量和病理学分辨率的数据。可以从组织中解剖或采样单个病变的模型还可以提供关于病变特异性细菌负荷和病变特异性药物浓度的数据。通过纳入医学成像，还可以随时间确定化合物对个体病变和动物内病理学分辨率的影响。结合药物暴露和药物在动物及其组织中的分布的测量对于选择最佳化合物以推向临床和开发更好的方案是重要的。我们回顾了每种模式的实际方面和每种模式的优点和局限性，以促进选择一个合理的组合，他们的化合物的发展。
Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a small proportion harbor Mycobacterium tuberculosis (Mtb) strains that have become resistant to drugs in the standard regimen. Development and approval of new drugs for TB have accelerated in the last 10 years, but more drugs are needed due to both Mtb’s development of resistance and the desire to shorten therapy to 4 months or less. The drug development process needs predictive animal models that recapitulate the complex pathology and bacterial burden distribution of human disease. The human host response to pulmonary infection with Mtb is granulomatous inflammation usually resulting in contained lesions and limited bacterial replication. In those who develop progressive or active disease, regions of necrosis and cavitation can develop leading to lasting lung damage and possible death. This review describes the major vertebrate animal models used in evaluating compound activity against Mtb and the disease presentation that develops. Each of the models, including the zebrafish, various mice, guinea pigs, rabbits, and non-human primates provides data on number of Mtb bacteria and pathology resolution. The models where individual lesions can be dissected from the tissue or sampled can also provide data on lesion-specific bacterial loads and lesion-specific drug concentrations. With the inclusion of medical imaging, a compound’s effect on resolution of pathology within individual lesions and animals can also be determined over time. Incorporation of measurement of drug exposure and drug distribution within animals and their tissues is important for choosing the best compounds to push toward the clinic and to the development of better regimens. We review the practical aspects of each model and the advantages and limitations of each in order to promote choosing a rational combination of them for a compound’s development.
影响因子：
2.4
作者：
Min F;Zhang Y;Pan J;Wang J;Yuan W
通讯作者：
Yuan W
结核病研究中的显微解剖方法。
影响因子：
0.7
作者：
Hudock TA;Lackner AA;Kaushal D
通讯作者：
Kaushal D