Ancestral antibiotic resistance in Mycobacterium tuberculosis
Ancestral antibiotic resistance in Mycobacterium tuberculosis
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DOI：
10.1073/pnas.0505446102
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发表时间：
2005-08-23
影响因子：
11.1
通讯作者：
Thompson, CJ
中科院分区：
文献类型：
--
作者：
Morris, RP;Nguyen, L;Thompson, CJ
结核分枝杆菌对大多数临床应用的抗生素的内在耐药性严重限制了治疗结核病的化学疗法选择。这种抵抗力部分是由其独特的细胞包膜的低渗透性提供的。在这里，我们描述了一个互补的系统，协调耐药性的药物已经穿透包膜，使分枝杆菌耐受不同类别的抗生素，抑制细胞质的目标。该系统依赖于whiB7，这是致病性分枝杆菌与链霉菌共有的一个基因，链霉菌是一种遗传学上相关的属，被称为多种抗生素的来源。In M. whiB7是由亚抑制浓度的抗生素（红霉素、四环素和链霉素）诱导的，并且whiB7无效突变体（链霉菌属和分枝杆菌属）在体外对抗生素超敏感。M.结核病在单核细胞模型系统内也是抗生素敏感的。除抗生素外，whiB7还通过暴露于致病性分枝杆菌物种可能在体内积累或在感染期间在真核宿主内遇到的脂肪酸而诱导。基因表达谱分析表明，whiB7转录决定通过激活包括参与核糖体保护和抗生素外排的基因的调节子的表达的耐药性。whiB7系统的组分可以作为鉴定使M.结核病或多药耐药衍生物更敏感。
Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection. Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render M. tuberculosis or multidrug-resistant derivatives more antibiotic-sensitive.