Putative Compensatory Mutations in the rpoC Gene of Rifampin-Resistant Mycobacterium tuberculosis Are Associated with Ongoing Transmission
Putative Compensatory Mutations in the rpoC Gene of Rifampin-Resistant Mycobacterium tuberculosis Are Associated with Ongoing Transmission
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DOI：
10.1128/aac.01541-12
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发表时间：
2013-02-01
影响因子：
4.9
通讯作者：
Victor, T. C.
中科院分区：
文献类型：
--
作者：
de Vos, M.;Mueller, B.;Victor, T. C.
结核分枝杆菌临床分离株的利福平耐药主要是由于rpoB基因81 bp利福平耐药决定区突变的细菌变体的选择而产生的。虽然这些突变被证明在没有抗生素压力的情况下推断适应性成本，但rpoA和rpoC的补偿性突变被确定为恢复携带rpoB突变的利福平耐药细菌的适应性。为了调查这些代偿性突变的流行病学相关性，我们分析了来自南非西开普省的286株耐药结核分枝杆菌和54株药敏结核分枝杆菌，该地区是耐多药结核病的高发地区。对rpoC基因RpoA-RpoC相互作用区域的部分测序显示，23.5%的利福平耐药菌株在该区域携带非同义突变。这些假定的rpoC代偿性突变与传播有关，因为在所有具有IS6110限制性片段长度多态性（RFLP）模式的利福平耐药菌株中，有30.8%属于公认的RFLP簇，其中含有假定的rpoC突变。具有独特RFLP模式的利福平耐药株中仅有9.4%存在这种突变（P < 0.01）。此外，这些假定的代偿性突变与特定菌株的基因型和rpoB S531L利福平抗性突变有关。在携带rpoB突变的分离株中，44.1%的分离株携带rpoC突变，而携带其他rpoB突变的分离株中，只有4.1%的分离株携带rpoC突变（P < 0.001）。我们的研究支持了rpoC突变在耐多药结核病传播中的作用，并说明了耐药突变、代偿突变和不同菌株遗传背景之间的上位性相互作用如何影响耐药结核分枝杆菌的代偿进化。
Rifampin resistance in clinical isolates of Mycobacterium tuberculosis arises primarily through the selection of bacterial variants harboring mutations in the 81-bp rifampin resistance-determining region of the rpoB gene. While these mutations were shown to infer a fitness cost in the absence of antibiotic pressure, compensatory mutations in rpoA and rpoC were identified which restore the fitness of rifampin-resistant bacteria carrying mutations in rpoB. To investigate the epidemiological relevance of these compensatory mutations, we analyzed 286 drug-resistant and 54 drug-susceptible clinical M. tuberculosis isolates from the Western Cape, South Africa, a high-incidence setting of multidrug-resistant tuberculosis. Sequencing of a portion of the RpoA-RpoC interaction region of the rpoC gene revealed that 23.5% of all rifampin-resistant isolates tested carried a nonsynonymous mutation in this region. These putative compensatory mutations in rpoC were associated with transmission, as 30.8% of all rifampin-resistant isolates with an IS6110 restriction fragment length polymorphism (RFLP) pattern belonging to a recognized RFLP cluster harbored putative rpoC mutations. Such mutations were present in only 9.4% of rifampin-resistant isolates with unique RFLP patterns (P < 0.01). Moreover, these putative compensatory mutations were associated with specific strain genotypes and the rpoB S531L rifampin resistance mutation. Among isolates harboring this rpoB mutation, 44.1% also harbored rpoC mutations, while only 4.1% of the isolates with other rpoB mutations exhibited mutations in rpoC (P < 0.001). Our study supports a role for rpoC mutations in the transmission of multidrug-resistant tuberculosis and illustrates how epistatic interactions between drug resistance-conferring mutations, compensatory mutations, and different strain genetic backgrounds might influence compensatory evolution in drug-resistant M. tuberculosis.