1] Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA [2] Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA.
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA.
Nat Commun. 2014 Jun 30;5:4306. doi: 10.1038/ncomms5306.
Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb's ICLs in antioxidant defense as a mechanism of antibiotic tolerance.
结核分枝杆菌（Mtb）是一种持久的细胞内病原体，对大多数抗生素具有内在的耐受性。然而，介导这种耐受性的特定因素仍不完全明确。在这里，我们应用代谢组学分析来发现与三种临床使用的抗结核药物异烟肼、利福平、链霉素的活性相关的一组常见代谢变化。尽管针对不同的细胞过程，这三种药物都触发了 Mtb 的异柠檬酸裂解酶（ICLs）的激活，这些代谢酶通常被认为参与补充三羧酸（TCA）循环中间产物。我们进一步表明，ICL 缺陷型 Mtb 菌株对所有三种抗生素的敏感性明显高于野生型 Mtb，并且当 Mtb 与抗氧化剂共同孵育时，这种敏感性可以通过化学方法得到挽救。这些结果表明，Mtb 的 ICLs 在抗氧化防御中作为抗生素耐受性的一种机制，具有以前未描述的作用。
