A role for 16S rRNA dimethyltransferase (ksgA) in intrinsic clarithromycin resistance in Mycobacterium tuberculosis
A role for 16S rRNA dimethyltransferase (ksgA) in intrinsic clarithromycin resistance in Mycobacterium tuberculosis
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DOI：
10.1016/j.ijantimicag.2013.02.011
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发表时间：
2013-06-01
影响因子：
10.8
通讯作者：
Prammananan, Therdsak
中科院分区：
文献类型：
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作者：
Phunpruch, Saranya;Warit, Saradee;Prammananan, Therdsak
广泛耐药结核病(XDR-TB)的出现使结核病的控制变得困难。因此，迫切需要开发新的抗结核病药物。或者，已经在人类身上用作抗感染药物并后来发现具有抗结核活性的药物可能会作为抗结核病药物使用，特别是针对耐药结核病。克拉霉素(CLR)是一种14元大环内酯类化合物和蛋白质合成抑制剂，对除结核分枝杆菌外的大多数分枝杆菌感染都有很强的抑制作用。由于可诱导ERM甲基酶(ErmMT)的存在，结核分枝杆菌对CLR[最低抑菌浓度(MIC)为8-16微克/毫升]具有天然抗药性。为了进一步了解结核分枝杆菌对CLR先天耐药的机制，通过转座子诱变获得了对CLR敏感的结核分枝杆菌H37Rv突变株。进一步研究发现，KsgA(Rv1010)被转座子灭活。KsgA基因编码16S rRNA腺嘌呤二甲基转移酶，甲基化16S rRNA的A1518和A1519(大肠杆菌编号)，在核糖体的生物发生中发挥重要作用。TN-196突变体与野生型KsgA基因的互补恢复了结核分枝杆菌的抗性表型(MIC为8-16微克/毫升)，证实了KsgA与结核分枝杆菌固有的CLR耐药性之间的关联。(C)2013年爱思唯尔公司和国际化疗学会。版权所有。
The emergence of extensively drug-resistant tuberculosis (XDR-TB) makes the control of tuberculosis (TB) difficult. As a result, there is an urgent need to develop new anti-TB drugs. Alternatively, drugs that have already been used in humans as anti-infectives and later found to have antitubercular activity might be useful as anti-TB drugs, particularly against drug-resistant TB. Clarithromycin (CLR), a 14-membered macrolide and protein synthesis inhibitor, has potent activity against most mycobacterial infections, except Mycobacterium tuberculosis. Mycobacterium tuberculosis is naturally resistant to CLR [ minimum inhibitory concentration (MIC) of 8-16 mu g/mL] owing to the presence of inducible erm methylase (ErmMT). With a view to gaining further insight into the mechanisms of innate CLR resistance in M. tuberculosis, CLR-susceptible M. tuberculosis H37Rv mutants were generated by transposon mutagenesis. One mutant, designated as Tn-196, was further investigated and it was found that ksgA (Rv1010) was inactivated by the transposon. The ksgA gene encodes a 16S rRNA adenine dimethyltransferase that methylates A1518 and A1519 (Escherichia coli numbering) of 16S rRNA and plays an important role in ribosome biogenesis. Complementation of the Tn-196 mutant with a wild-type ksgA gene restored the resistant phenotype (MIC of 8-16 mu g/mL), corroborating the association of ksgA with intrinsic CLR resistance in M. tuberculosis. (C) 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.