Targeting Phenotypically Tolerant Mycobacterium tuberculosis.
Targeting Phenotypically Tolerant Mycobacterium tuberculosis.
复制标题
DOI：
10.1128/microbiolspec.tbtb2-0031-2016
复制
发表时间：
2017-01
影响因子：
3.7
通讯作者：
Nathan C
中科院分区：
文献类型：
--
作者：
Gold B;Nathan C
虽然免疫系统被认为是避免数十亿暴露于结核分枝杆菌的人患结核病的原因，但免疫系统也应该为调节抗生素提供快速持久治愈疾病的能力而负责。在患有结核病的个体中，宿主免疫产生不同的微环境生态位，这些微环境生态位支持M.结核细菌中的非复制生理状态与表型药物耐受性相关。许多这些宿主微环境，当在体外模拟碳饥饿，完全营养饥饿，固定相，酸性pH，活性氮中间体，缺氧，生物膜，并从链霉素成瘾菌株SS 18 b的链霉素，使M。结核病对临床环境中给予结核病患者的许多抗生素具有深刻的耐受性。靶向非复制型持续存在者预计将减少抗生素治疗的持续时间和治疗后复发率。一些有希望的治疗结核病的药物，如利福平和贝达喹啉，只能杀死非复制型M。结核病在体外的浓度远远大于其对复制杆菌的最小抑制浓度。目前迫切需要确定目前使用的抗生素，以及学术和企业筛选收集的分子，对非复制型M.结核为此，我们回顾了针对非复制型M的高通量筛选方法。结核病和发展候选分子的方法。一种基于已报道的杀死非复制型M的分子的结构和假定靶点的分类。结核病揭示了药效团的丰富多样性。然而，这些化合物中很少有在排除吸附化合物在试验恢复期作用的影响的条件下进行检测，并且很少有在一种以上的非复制条件下进行检测。非复制型分枝杆菌具有代谢活性，这一点通过其对几种抗生素和靶向脂质、RNA、DNA、蛋白质和肽聚糖合成的工具化合物的敏感性得到证实。
While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.