MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100176, Beijing, China.
Chinese Center for Disease Control and Prevention, 155# Changbai Road, Changping District, 102206, Beijing, China.
Emerg Microbes Infect. 2018 Nov 16;7(1):183. doi: 10.1038/s41426-018-0184-0.
Whole-genome sequencing was used to analyze the profiles of isoniazid (INH) resistance-related mutations among 188 multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and mono-INH-resistant isolates collected in a recent Chinese national survey. Mutations were detected in 18 structural genes and two promoter regions in 96.8% of 188 resistant isolates. There were high mutation frequencies in katG, the inhA promoter, and ahpC-oxyR regulator regions in INH-resistant isolates with frequencies of 86.2%, 19.6%, and 18.6%, respectively. Moreover, a high diversity of mutations was identified as 102 mutants contained various types of single or combined gene mutations in the INH-resistant group of isolates. The cumulative frequencies of katG 315 or inhA-P/inhA mutations was 68.1% (128/188) for the INH-resistant isolates. Of these isolates, 46 isolates (24.5% of 188) exhibited a high level of resistance. A high level of resistance was also observed in 21 isolates (11.2% of 188) with single ahpC-oxyR mutations or a combination of ahpC-oxyR and katG non-315 mutations. The remaining 17 mutations occurred sporadically and emerged in isolates with combined katG mutations. Such development of INH resistance is likely due to an accumulation of mutations under the pressure of drug selection. Thus, these findings provided insights on the levels of INH resistance and its correlation with the combinatorial mutation effect resulting from less frequent genes (inhA and/or ahpC). Such knowledge of other genes (apart from katG) in high-level resistance will aid in developing better strategies for the diagnosis and management of TB.
全基因组测序用于分析最近在中国全国性调查中收集的 188 株耐多药结核分枝杆菌(MDR-TB)和单异烟肼耐药分离株中异烟肼(INH)耐药相关突变的特征。在 188 株耐药分离株中,检测到 18 个结构基因和两个启动子区域的突变,占 96.8%。在 INH 耐药分离株中,katG、inhA 启动子和 ahpC-oxyR 调节剂区域的突变频率很高,分别为 86.2%、19.6%和 18.6%。此外,在 INH 耐药组分离株中发现了高度多样化的突变,102 个突变体包含各种类型的单个或组合基因突变。katG 315 或 inhA-P/inhA 突变的累积频率在 INH 耐药分离株中为 68.1%(128/188)。在这些分离株中,46 株(188 株的 24.5%)表现出高度耐药。21 株(188 株的 11.2%)仅存在 ahpC-oxyR 突变或 ahpC-oxyR 和 katG 非 315 突变的组合也表现出高度耐药。其余 17 种突变是偶然发生的,出现在合并 katG 突变的分离株中。这种 INH 耐药性的发展可能是由于药物选择压力下突变的积累。因此,这些发现提供了 INH 耐药水平及其与来自较少频繁基因(inhA 和/或 ahpC)的组合突变效应的相关性的见解。对高水平耐药性中其他基因(除 katG 外)的了解将有助于制定更好的策略来诊断和管理结核病。