Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism.
Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism.
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由巨噬细胞诱导的外排机制介导的复制分枝杆菌的药物耐受性。
DOI：
10.1016/j.cell.2011.02.022
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发表时间：
2011-04-01
期刊：
影响因子：
64.5
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Adams KN;Takaki K;Connolly LE;Wiedenhoft H;Winglee K;Humbert O;Edelstein PH;Cosma CL;Ramakrishnan L
结核病是一种复杂的肉芽肿性疾病，其治疗需要长期的多药治疗以克服耐受性，这是一种广泛归因于非复制细菌亚群的表观遗传耐药性。在这里，我们部署海分枝杆菌感染的斑马鱼幼虫体内抗结核药物活性和耐受性的表征。我们描述了多药耐药生物体的存在，这些生物体在感染后几天内出现，在复制的细胞内种群中富集，并通过结核性肉芽肿放大和传播。细胞内生长所需的细菌外排泵介导这种巨噬细胞诱导的耐受性。当结核分枝杆菌感染培养的巨噬细胞时，这种新发现的耐受性群体也会发展，这表明它有助于人类结核病的药物耐受性负担。外排泵抑制剂如维拉帕米可降低这种耐受性。因此，在标准抗结核治疗中加入这种目前批准的药物或更特异的抑制剂可能会缩短治愈性治疗的持续时间。
Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multi-drug tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This newly discovered tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug, or more specific inhibitors, to standard antitubercular therapy may shorten the duration of curative treatment.
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