Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes.
Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes.
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DOI：
10.1038/ng.2743
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发表时间：
2013-10
期刊：
影响因子：
30.8
通讯作者：
Alland D
中科院分区：
文献类型：
--
作者：
Safi H;Lingaraju S;Amin A;Kim S;Jones M;Holmes M;McNeil M;Peterson SN;Chatterjee D;Fleischmann R;Alland D
为了研究耐药性的演变，我们从遗传学和生物化学方面对体外筛选出的结核分枝杆菌菌株进行了乙胺丁醇耐药性鉴定。十异戊二烯磷酰基-β-d-阿拉伯糖（DPA）生物合成和利用途径基因Rv 3806 c、Rv 3792、embB和embC的突变累积产生了广泛的乙胺丁醇最小抑制浓度（MIC），这取决于突变类型和数量。Rv 3806 c突变增加DPA合成，导致野生型背景中MIC从2 μg/ml增加到4 μg/ml，在embB密码子306突变体背景中从16 μg/ml增加到32 μg/ml。Rv 3792中的同义突变增加了下游embC（乙胺丁醇靶点）的表达，导致MIC为8 µg/ml。高水平的抗性需要多步选择。在最高抗性水平下观察到embC突变或非常高的embC表达。在临床分离株中，Rv 3806 c突变与高水平耐药性相关，并与embB突变对MIC具有倍增效应。乙胺丁醇耐药性是通过获得以复杂方式相互作用的突变来获得的，这些突变产生一系列MIC，从低于断点值的MIC到代表高水平耐药性的MIC。
To study the evolution of drug resistance, we genetically and biochemically characterized Mycobacterium tuberculosis strains selected in vitro for ethambutol resistance. Mutations in decaprenylphosphoryl-β-d-arabinose (DPA) biosynthetic and utilization pathway genes Rv3806c, Rv3792, embB and embC accumulated to produce a wide range of ethambutol minimal inhibitory concentrations (MICs) that depended on mutation type and number. Rv3806c mutations increased DPA synthesis, causing MICs to double from 2 to 4 µg/ml in a wild-type background and to increase from 16 to 32 µg/ml in an embB codon 306 mutant background. Synonymous mutations in Rv3792 increased the expression of downstream embC, an ethambutol target, resulting in MICs of 8 µg/ml. Multistep selection was required for high-level resistance. Mutations in embC or very high embC expression were observed at the highest resistance level. In clinical isolates, Rv3806c mutations were associated with high-level resistance and had multiplicative effects with embB mutations on MICs. Ethambutol resistance is acquired through the acquisition of mutations that interact in complex ways to produce a range of MICs, from those falling below breakpoint values to ones representing high-level resistance.
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影响因子：
2.8
作者：
Huang, Hairong;Berg, Stefan;McNeill, Michael R.
通讯作者：
McNeill, Michael R.
影响因子：
30.8
作者：
Comas, Inaki;Borrell, Sonia;Roetzer, Andreas;Rose, Graham;Malla, Bijaya;Kato-Maeda, Midori;Galagan, James;Niemann, Stefan;Gagneux, Sebastien
通讯作者：
Gagneux, Sebastien
影响因子：
4.9
作者：
Goude, R.;Amin, A. G.;Parish, T.
通讯作者：
Parish, T.
影响因子：
5.2
作者：
Plinke, Claudia;Cox, Helen S.;Niemann, Stefan
通讯作者：
Niemann, Stefan
DOI：
10.1016/s0732-8893(03)00132-9
发表时间：
2003-11-01
影响因子：
2.9
作者：
Kim, SY;Park, YJ;Kang, CS
通讯作者：
Kang, CS