Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC-46A polymorphism
Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates from England and Wales reveals the phylogenetic significance of the ahpC-46A polymorphism
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DOI：
10.1128/aac.49.4.1455-1464.2005
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发表时间：
2005-04-01
影响因子：
4.9
通讯作者：
Drobniewski, FA
中科院分区：
文献类型：
--
作者：
Baker, LV;Brown, TJ;Drobniewski, FA
本研究调查了最常见的与异烟肼耐药相关的突变katG 315Thr、katG 315Asn、inha-15T、inha-8A和oxR-ahpC基因间隔区的患病率和诊断潜力，对来自英格兰和威尔士的202株耐异烟肼结核分枝杆菌菌株和176株随机选择的完全敏感菌株进行了定向寡核苷酸阵列和有限DNA测序鉴定。这些菌株是从来自29个国家的患者身上恢复的；41个分离株具有多重耐药性。169株不同的异烟肼耐药株中，影响katG315、inhA启动子和oxR-ahpC基因间隔区的突变分别为62.7%、21.9%和30%，而敏感株分别为0、0和8%。每个基因座的突变频率与耐药谱或既往抗结核药物治疗无关。OxR-ahpC基因间隔区的最常见突变ahpC-46A存在于23.7%的异烟肼耐药株和7.5%的敏感株中。这是起源于印度次大陆的结核分枝杆菌亚群的一个系统发育标记，它与德里株和中亚株CASI具有相同的IS6110限制性片段长度多态和孢子型特征；该标记与异烟肼耐药性和katG 315Thr突变密切相关。总体而言，82.8%的无关异烟肼耐药分离株可以通过分析两个基因座来鉴定：katG315和inha启动子。对oxR-ahpC基因间隔区的分析虽然在系统发生学上很有意义，但对进一步鉴定异烟肼耐药菌株并没有太大帮助。
The present study investigated the prevalence and diagnostic potential of the most commonly reported mutations associated with isoniazid resistance, katG 315Thr, katG 315Asn, inhA -15T, inhA -8A, and the oxyR-ahpC intergenic region, in a population sample of 202 isoniazid-resistant Mycobacterium tuberculosis isolates and 176 randomly selected fully sensitive isolates from England and Wales identified by using a directed oligonucleotide array and limited DNA sequencing. The strains were recovered from patients originating from 29 countries; 41 isolates were multidrug resistant. Mutations affecting katG 315, the inhA promoter, and the oxyR-ahpC intergenic region were found in 62.7, 21.9, and 30% of 169 genotypically distinct isoniazid-resistant isolates, respectively, whereas they were found in 0, 0, and 8% of susceptible strains, respectively. The frequency of mutation at each locus was unrelated to the resistance profile or previous antituberculous drug therapy. The commonest mutation in the oxyR-ahpC intergenic region, ahpC -46A, was present in 23.7% of isoniazid-resistant isolates and 7.5% of susceptible isolates. This proved to be a phylogenetic marker for a subgroup of M. tuberculosis strains originating on the Indian subcontinent, which shared IS6110-based restriction fragment length polymorphism and spoligotype features with the Delhi strain and Central Asian strain CASI; and this marker is strongly associated with isoniazid resistance and the katG 315Thr mutation. In total, 82.8% of unrelated isoniazid-resistant isolates could be identified by analysis of just two loci: katG 315 and the inhA promoter. Analysis of the oxyR-ahpC intergenic region, although phylogenetically interesting, does not contribute significantly to further identification of isoniazid-resistant isolates.