耐多药和广泛耐药MTB的inhA基因突变与对丙硫异烟胺耐药的相关性分析

Correlation analysis between inhA gene mutation and protionamide-resistance in multidrug resistance and extensively drug-resistant Mycobacterium tuberculosis

目的 了解耐多药（MDR）和广泛耐药（XDR）结核分枝杆菌（MTB）katG和inhA基因突变特征及其与对丙硫异烟胺（PTH）耐药的相关性.方法 选取2016年2月至2017年2月首都医科大学附属北京胸科医院确诊的132例MDR-TB或XDR-TB患者作为研究对象.研究对象临床分离株均培养阳性且鉴定为MTB,具有异烟肼（INH）、利福平（RFP）、左氧氟沙星（Lfx）、阿米卡星（Am）、卷曲霉素（Cm）及PTH的药物敏感性试验（简称＂药敏试验＂）结果,同时具有katG和inhA突变检测结果.分析MTB临床分离株katG和inhA突变特征及对PTH耐药的相关性.结果 132株临床分离菌株中MDR-MTB有89株（67.4%）、前广泛耐药结核分枝杆菌（pre-XDR-MTB）有26株（19.7%）、XDR-MTB有17株（12.9%）.菌株对PTH的总耐药率为22.7%（30/132）,在MDR-MTB、pre-XDR-MTB、XDR-MTB中分别为11.2%（10/89）、30.8%（8/26）、70.6%（12/17）.XDR-MTB对PTH的耐药率明显高于MDR-MTB（χ^2=30.57,P〈0.01）和pre-XDR-MTB（χ^2=6.55,P〈0.05）.inhA突变率（合并及不合并katG突变）在MDR-MTB、pre-XDR-MTB、XDR-MTB中分别为19.1%（17/89）、23.1%（6/26）、17.6%（3/17）.在MDR-MTB、pre-XDR-MTB、XDR-MTB的PTH耐药株中,只有5/10、4/8、3/12发生inhA基因突变. 结论 从MDR-MTB到XDR-MTB临床分离株,对PTH的耐药率明显增加,inhA基因突变率下降,inhA突变可能不是XDR-MTB对PTH耐药的主要原因,未检测到inhA突变的菌株并不一定对PTH敏感.

Objective To investigate the characteristics of mutations in genes katG and inhA and their association with resistance to protionamide （PTH） in the clinical strains of multidrug resistance Mycobacterium tuberculosis （MDR-MTB） and extensively drug-resistant Mycobacterium tuberculosis （XDR-MTB）.Methods A total of 132 patients with MDR-TB or XDR-TB diagnosed in Beijing Chest Hospital, Capital Medical University from February 2016 to February 2017 were selected as the subjects of this study. The clinical isolates of these subjects were culture-positive and identified as MTB. The results of drug sensitivity test for isoniazid （INH）, rifampicin （RFP）, levofloxacin （Lfx）, amikacin （Am）, capreomycin （Cm） and PTH and the data of mutations in katG and inhA were available. The characteristics of katG and inhA mutations in MTB clinical isolates and their correlation with resis-tance to PTH were analyzed.Results Among the 132 clinical isolates, 89 （67.4%） were MDR-MTB, 26 （19.7%） were pre-XDR-MTB and 17 （12.9%） were XDR-MTB. The total resistance rate of PTH was 22.7% （30/132）, and the rates were 11.2% （10/89）, 30.8% （8/26） and 70.6% （12/17） in MDR-MTB, pre-XDR-MTB and XDR-MTB, respectively. The resistance rate of XDR-MTB to PTH was significantly higher than that of MDR-MTB （χ^2=30.57, P〈0.01） and pre-XDR-MTB （χ^2=6.55, P〈0.05）. The mutation rate of inhA （with or without katG mutation） was 19.1% （17/89）, 23.1% （6/26） and 17.6% （3/17） in MDR-MTB, pre-XDR-MTB and XDR-MTB strains, respectively. In PTH resistant strains of MDR-MTB, pre-XDR-MTB and XDR-MTB, only 5/10, 4/8 and 3/12 had inhA gene mutation. Conclusion From MDR-MTB to XDR-MTB clinical strains, the proportion of PTH resistance was increased significantly, and the mutation rate of inhA gene was decreased. The mutation in inhA gene may not be the main molecular mechanism of PTH resistance in XDR-MTB, and the strains without inhA mutation are not sure to be sensitive to PTH.