Methyltransferase Erm(37) slips on rRNA to confer atypical resistance in Mycobacterium tuberculosis
Methyltransferase Erm(37) slips on rRNA to confer atypical resistance in Mycobacterium tuberculosis
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DOI：
10.1074/jbc.m505727200
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发表时间：
2005-11-25
影响因子：
4.8
通讯作者：
Douthwaite, S
中科院分区：
文献类型：
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作者：
Madsen, CT;Jakobsen, L;Douthwaite, S
结核分枝杆菌复合体的成员具有耐药性决定因子erm(37)（也称为ermMT），这是在多种产药细菌和致病菌中发现的erm基因的截断同源物。迄今为止检测的所有erm基因编码N-6-单甲基转移酶或N-6， N-6-二甲基转移酶，在23s rRNA中显示核苷酸A2058的绝对特异性。A2058的单甲基化使其对大环内酯类、利可沙胺类和链状gramin B （MLSB）类抗生素产生耐药性，而对最新的大环内酯类衍生物酮内酯类没有耐药性。A2058位点的二甲基化使其对所有MLSB和酮类药物具有高耐药性。erm（37）表型不属于这两种类型。我们在这里通过串联质谱分析显示，Erm（37）最初在其主要靶点A2058上添加了一个甲基，然后在邻近的核苷酸A2057和A2059上附加了额外的甲基。其他甲基转移酶Erm(E)和Erm(O)在分枝杆菌rRNA上保持对A2058的特异性。Erm(E)和Erm(O)具有全长c端结构域，这似乎对稳定甲基转移酶在其rRNA靶点上的作用很重要，并且该结构域在Erm中被截断（37）。结核分枝杆菌Erm（37）与其rRNA的松散相互作用产生独特的甲基化模式，并赋予对酮类药物特利霉素的抗性。
Members of the Mycobacterium tuberculosis complex possess a resistance determinant, erm(37) (also termed ermMT), which is a truncated homologue of the erm genes found in a diverse range of drug-producing and pathogenic bacteria. All erm genes examined thus far encode N-6-monomethyltransferases or N-6, N-6-dimethyltransferases that show absolute specificity for nucleotide A2058 in 23 S rRNA. Monomethylation at A2058 confers resistance to a subset of the macrolide, lincosamide, and streptogramin B (MLSB) group of antibiotics and no resistance to the latest macrolide derivatives, the ketolides. Dimethylation at A2058 confers high resistance to all MLSB and ketolide drugs. The erm(37) phenotype fits into neither category. We show here by tandem mass spectrometry that Erm(37) initially adds a single methyl group to its primary target at A2058 but then proceeds to attach additional methyl groups to the neighboring nucleotides A2057 and A2059. Other methyltransferases, Erm(E) and Erm(O), maintain their specificity for A2058 on mycobacterial rRNA. Erm(E) and Erm(O) have a full-length C-terminal domain, which appears to be important for stabilizing the methyltransferases at their rRNA target, and this domain is truncated in Erm(37). The lax interaction of the M. tuberculosis Erm(37) with its rRNA produces a unique methylation pattern and confers resistance to the ketolide telithromycin.