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通讯作者:

张向荣,E-mail:6228222@qq.com

中图分类号:R52

文献标识码:A

文章编号:1007-4368(2023)03-392-05

DOI:10.7655/NYDXBNS20230314

参考文献 1
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参考文献 6
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参考文献 7
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参考文献 9
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参考文献 11
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参考文献 12
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参考文献 13
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参考文献 14
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参考文献 15
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参考文献 16
BAROZI V,MUSYOKA T M,SHEIK AMAMUDDY O,et al.Deciphering isoniazid drug resistance mechanisms on dimeric Mycobacterium tuberculosis KatG via post⁃molecu⁃ lar dynamics analyses including combined dynamic resi⁃ due network metrics[J].ACS Omega,2022,7(15):13313-13332
参考文献 17
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参考文献 18
NOROUZI F,MOGHIM S,FARZANEH S,et al.Signifi⁃ cance of the coexistence of non ⁃ codon 315 katG,inhA,and oxyR⁃ahpC intergenic gene mutations among isoniazid ⁃resistant and multidrug⁃resistant isolates of Mycobacterium tuberculosis:a report of novel mutations[J].Pathog Glob Health,2022,116(1):22-29
参考文献 19
VERMA H,NAGAR S,VOHRA S,et al.Genome analy⁃ ses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal po⁃ tential drug targets[J].Microb Genom,2021,7(3):000542
参考文献 20
NIETO R L M,MEHAFFY C,CREISSEN E,et al.Viru⁃ lence of Mycobacterium tuberculosis after acquisition of isoniazid resistance:individual nature of katG mutants and the possible role of AhpC[J].PLoS One,2016,11(11):0166807
参考文献 21
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目录contents

    摘要

    目的:了解结核分枝杆菌(Mycobacterium tuberculosis,MTB)katG、inhA和AhpC基因突变与异烟肼(isoniazid,INH)耐药的相关性。方法:回顾性分析南京市第二医院结核科2019年1月—2021年12月住院肺结核患者MTB培养及耐药基因检测结果。结果:痰或灌洗液MTB培养及菌种鉴定为人型结核分枝杆菌1712例,INH表型药敏测定,敏感1308例,耐药404例;其中663例标本同时送检INH耐药基因检测(分子药敏),99例未检出,564例分子药敏阳性,其中敏感390例,突变174例,突变位点为katG315、inhA启动子和AhpC启动子。以表型药敏作为金标准,分子药敏检出INH耐药的灵敏度为92.4%(95%CI:88.5% ~96.4%),特异度为96.2%(95%CI:94.3%~98.1%),阳性预测值为91.4%(95%CI:87.2%~95.5%),阴性预测值为96.7%(95%CI: 94.9%~98.4%),约登指数88.6%,准确率95.0%。172例表型药敏为耐药的患者检出耐药基因突变159例,分别为katG315突变 126 次,inhA 启动子突变 25 次和 AhpC 启动子突变 15 次,katG315 突变的发生率显著高于 inhA 和 AhpC 启动子(χ2 =123.915、 151.891,P<0.001)。52 例表型药敏为高度耐药的患者,katG315 突变 41 次,inhA 启动子突变 8 次,AhpC 启动子突变 7 次, katG315突变率显著高于inhA和AhpC启动子(χ2 =39.510、42.146,P<0.001)。katG315联合inhA/AhpC启动子突变菌株的高度耐药率明显高于 katG315 单独突变菌株(χ2 =4.951,P=0.045)。耐多药组和准广泛耐药组 katG315 突变率显著高于耐 INH 组(χ2 =5.522,P=0.018;χ2 =8.422,P=0.007)。准广泛耐药组 katG315 联合 inhA/AhpC 启动子的突变率显著升高(χ2 =8.916,P= 0.006)。结论:katG315是本地区INH耐药的主要突变位点,与INH高度耐药密切相关。

  • 尽管抗结核药物的治疗有效,但结核病依然威胁着人类健康。结核分枝杆菌(Mycobacterium tuberculosis,MTB)耐药菌株的出现和传播是阻碍该病控制的因素之一。WHO估计,在全球范围内,2020年有990万人患结核病,相当于每10万人中有127例,其中人类免疫缺陷病毒(human immunodeficiency virus,HIV)阴性的结核病患者死亡 130 万人[1]。 2020 年全球有 71%经细菌学确诊的肺结核患者接受了利福平耐药性检测,发现了耐多药/耐利福平结核病和广泛耐药结核病,总数为157 903例,而耐药结核病治愈率仅为45%[2],耐多药结核病的出现造成了严重的公共卫生危机和威胁。因此,早期发现耐药结核病是制止耐多药结核病发展的一项有效策略。既往痰培养及药敏实验被认为是耐药结核病诊断的金标准,但耗时长,需 2~3 个月才能有结果。近年来多种快速分子检测方法出现[3],为早期发现耐多药结核病提供了解决方案。异烟肼(isoni⁃ azid,INH)是抗结核治疗中一个不可或缺的主药。文献报道INH 耐药与katG、inhA、AhpC 等基因突变密切相关[4-5]。为了解南京地区INH耐药与基因突变的相关性,本研究回顾性分析了近3年来南京中医药大学附属南京医院结核科住院的肺结核患者抗结核治疗前MTB培养及INH耐药基因检测结果,现报道如下。

  • 1 对象和方法

  • 1.1 对象

  • 2019 年 1 月—2021 年 12 月南京中医药大学附属南京医院结核科住院患者治疗前送检痰或灌洗液标本8 246例行MTB 培养,结果2 252例阳性,通过菌种鉴定发现人型结核分枝杆菌1 712例,行INH 表型药敏检测,其中有663例同时送检INH分子药敏检验。根据WHO使用的5个类别对耐药结核病进行分类[1]:耐INH结核病、耐利福平结核病、耐多药结核病、准广泛耐药结核病和广泛耐药结核病。耐INH结核病是只对INH耐药,对其他一线、二线结核药物均敏感的结核病;准广泛耐药结核病是对利福平和任何氟喹诺酮类药物(一类、二线抗结核药物)具有耐药性的结核病;广泛耐药结核病是对利福平、任何氟喹诺酮类药物以及贝达喹啉和利奈唑胺中的至少一种具有耐药性的结核病。由于南京中医药大学附属南京医院无法检测贝达喹啉和利奈唑胺表型药敏,因此本研究把研究人群分为耐 INH、耐多药和准广泛耐药3类。所有患者HIV检测均为阴性。本研究经医院伦理委员会批准,所有患者知情同意。

  • 1.2 方法

  • 1.2.1 MTB培养及表型药敏鉴定

  • 采用 MTB 改良罗氏或 BACTECMGIT960 行 MTB培养,利用PNB培养基能够抑制牛分枝杆菌以及结核分枝杆菌但不能抑制非结核分枝杆菌、TCH 培养基能抑制牛结核分支杆菌但不能抑制结核分枝杆菌以及非结核分枝杆菌的特点,进行阳性标本的菌种鉴定。对培养和鉴定出的人型结核分枝杆菌菌株采用绝对浓度法固体药敏试验检测 INH 耐药性,设置高、低两个 INH 浓度(分别为 10 μg/mL 和 1 μg/mL),取菌液 0.1 mL,分别接种至两支对照管(中性改良罗氏培养基)和高浓度、低浓度含药培养基的表面。菌落生长<20个菌落,报告为实际菌落数;菌落生长占斜面面积1/4为耐药1+;菌落生长占斜面面积1/2为耐药2+;菌落生长占斜面面积3/4 为耐药3+;全斜面生长,菌落融合为耐药4+。被检菌株在无药对照培养基上生长良好、含药培养基斜面无菌落生长为敏感;生长菌落≥20个为耐药。高浓度和低浓度含药培养基均耐药为高度耐药,仅低浓度含药培养基耐药为低度耐药。

  • 1.2.2 荧光 PCR 检测 INH 耐药基因进行分子药敏判断

  • 使用厦门至善生物科技有限公司生产的针对 INH的MTB耐药突变检测试剂盒,严格按照说明书操作。将送检的MTB菌株提取的DNA经扩增和熔解曲线分析后,通过检测标本与野生型阳性对照退火温度(Tm)峰值的差异,判断是否耐药。标本4个通道的Tm值均与阳性对照的Tm值误差不超过1℃,判断为野生型,为分子药敏敏感;标本4个通道任一通道的Tm值与阳性对照相差2℃或以上,判断为突变型,为分子药敏耐药。

  • 1.3 统计学方法

  • 采用SPSS26.0进行统计分析,计数资料用百分率表示,两组间比较采用卡方检验或Fisher精确概率检验(n<40或T<1),等级资料组间比较行Kruskal ⁃Wallis秩和检验,P<0.05为差异有统计学意义。

  • 2 结果

  • 2.1 表型药敏与分子药敏结果的比较

  • 1712 例行表型药敏测定,敏感 1 308 例,耐药 404例。663例同时行表型药敏和分子药敏实验,分子药敏结果为99例未检出,检出阳性564例,检出率为85.1%,其中分子药敏结果敏感390例、耐药174例 (表1),耐药基因突变位点为 katG315、inhA 启动子和 AhpC 启动子。564 例表型及分子药敏均阳性的患者中,以表型药敏为金标准,分子药敏检出 INH 耐药的灵敏度为 92.4%(95%CI:88.5%~96.4%),特异度为 96.2%(95%CI:94.3%~98.1%),阳性预测值为 91.4%(95% CI:87.2%~95.5%),阴性预测值为 96.7%(95%CI:94.9%~98.4%),约登指数 88.6%,准确率 95.0%。表型药敏结果为敏感的 392 例中,分子药敏结果耐药15例(表1),其中耐药基因katG315 突变 18 次,inhA 启动子突变 5 次,AhpC 启动子突变 13 次,各位点突变率差异无统计学意义(χ2 = 0.632,P=0.825)。表型药敏结果为耐药的172例中,分子药敏检出耐药 159 例(表1),其中耐药基因 katG315突变126次,inhA启动子和AhpC启动子突变分别为25次和 15 次,katG315基因突变的发生率显著高于 inhA 启动子和 AhpC 启动子(χ2 =123.915、 151.891,P<0.001)。提示 katG315 基因突变与 INH 耐药密切相关。

  • 表1 表型药敏与分子药敏结果的比较

  • 2.2 分子药敏为耐药MTB的表型药敏结果

  • 174例分子药敏为耐药的患者中表型药敏为敏感的有 15 例,低度耐药 107 例,高度耐药 52 例(表2)。52例表型高度耐药中,检测出katG315突变共 41 次,inhA 突变共 8 次,AhpC 突变共 7 次,katG315 突变率显著高于 inhA 和 AhpC 启动子(χ2 =39.510、 42.146,P<0.001),提示katG315突变与INH高度耐药密切相关。表型药敏为耐药的 159 例中单纯 katG315 突变 116 例,其中表型高度耐药 37 例(37/ 116,31.9%)。katG315合并inhA/AhpC突变5例,其中表型高度耐药 4 例(4/5,80.0%),katG315 联合 inhA/AhpC启动子突变菌株的高度耐药率明显高于 katG315 单独突变菌株(χ2 =4.951,P=0.045),提示 inhA 和 AhpC 联合 katG315 突变可以协同提高 INH 的耐药程度。

  • 2.3 分子药敏为耐药MTB的耐药分类

  • 174例分子药敏为耐药的患者根据表型药敏结果按照WHO耐药分类分成耐INH组、耐多药组、准广泛耐药组(表3)。katG315 在各组间突变率差异有统计学意义(χ2 =9.093,P=0.011),组间比较发现耐多药组和准广泛耐药组的katG315突变率显著高于耐 INH 组(χ2 =5.522,P=0.018;χ2 =8.422,P= 0.007)。inhA/AhpC 启动子在各组间的突变率差异有统计学意义(χ2 =20.484,P <0.001),组间比较后发现耐INH组inhA/AhpC启动子的突变率显著高于耐多药组和准广泛耐药组(χ2 =5.522,P=0.029;χ2 = 20.859,P <0.001)。准广泛耐药组 katG315+inhA/ AhpC启动子的突变率显著升高(χ2 =8.916,P=0.006)。

  • 3 讨论

  • MTB介导的INH耐药机制非常复杂,与几个基因突变相关。INH是一种抗结核药物前体,需通过 katG编码一种过氧化氢酶过氧化物酶(catalase per⁃ oxidase,CP),将药物前体 INH 转化为超氧化物、一氧化氮等活性分子,然后攻击细胞内的多个药物靶点发挥药效。katG编码的CP是唯一能活化INH前体的酶。当katG基因发生点突变、碱基缺失或者插入时,CP活性下降或丧失,阻止INH变成活性形式,从而使MTB对INH产生不同程度的耐药[6]。katG突变,特别是Ser315Thr突变是全世界不同地区INH耐药的主要原因,其突变率为 42%~90%[7]。katG315 突变体的流行可能使 MTB 损失 CP 活性,反而赋予了其生存优势,导致其更容易在人群中传播[8]。其他基因如 inhA 也参与 INH 耐药。inhA 是脂肪酸合酶Ⅱ型系统的必需酶,可以将脂肪酸合酶Ⅰ型的 C16~C18 脂肪酸顺序延伸至 C56,从而产生菌酸前体,该前体是分枝杆菌包膜的主要脂质。在脂肪酸合酶Ⅱ型系统中,inhA以烟酰胺腺嘌呤二核苷酸辅因子为供氢体,催化脂肪底物羰基共轭的反式双键的还原。INH抑制inhA从而阻止脂肪酸的合成,最终导致 MTB 死亡[9]。12%~42%的耐 INH 菌株发生 inhA 启动子区突变,使 inhA 过表达,导致 MTB 对 INH低水平耐药[10]

  • 表2 174例分子药敏为耐药MTB的表型药敏结果

  • 表3 174例分子药敏为耐药MTB的耐药分类

  • 目前,katG315 和 inhA 作为快速检测 INH 耐药的标志,商业用试剂盒已被WHO推荐用于临床INH 耐药诊断。本研究采用厦门至善生物科技有限公司生产的针对INH的MTB耐药突变检测试剂盒,可以检测INH、利福平、乙胺丁醇、氟喹诺酮、二线注射剂耐药基因。本研究发现 INH 分子耐药检测的准确率高达 95.0%,目前此检测在临床上运用较广泛。本研究检测到3个INH耐药突变位点,分别为 katG315、inhA启动子和AhpC启动子,其中katG315 突变占 71%,远高于其他基因。katG315 还与高度耐药相关,katG315 在耐多药和准广泛耐药中的突变率也明显升高,提示katG315突变的MTB更容易对其他抗结核药物产生耐药。这可能由于 INH 耐药后抗结核治疗时间延长,促进了MTB对其他药物的耐药。也有文献报道katG315突变是2次突变的结果,长期不适当的治疗促进了该突变[11]。本研究还发现与单纯katG315突变比较,katG315联合inhA 或 AhpC 基因突变的高度耐药率明显增高,并且联合突变在准广泛耐药组的发生率显著升高,提示 inhA 或 AhpC 基因突变可以协同提高 katG 突变对 INH耐药的影响。既往文献报道,当inhA联合katG 突变时,MTB 抗 INH 能力显著增加[12],MTB 在治疗下可转变为广泛耐药MTB[13],同时增加患者不良结局与死亡风险[14]

  • MTB 对氧化应激的耐受性取决于CP酶,CP酶由KatG蛋白合成,因此,KatG本身能保护MTB免受 H2O2和其他活性氧物质的伤害[15]。KatG 基因突变导致KatG蛋白活性下降[16],不仅激活INH的能力受损[17],CP酶合成也受损,MTB自身抗氧化的功能受到威胁,那么MTB就需要通过替代过氧化物酶系统来补偿受损的抗氧化功能,克服氧化应激,以保持毒性,一些证据表明 AhpC 是实现这一作用的关键元素[18]。AhpC基因的过度表达,烷基氢过氧化物还原酶的产生增加,以避免有机过氧化物对菌体的伤害[19];因此,AhpC基因突变间接导致INH耐药。文献报道,INH耐药katG缺陷株和INH敏感株中均观察到 AhpC 突变[20]。本研究发现,katG 突变的菌株可合并AhpC突变,且AhpC突变能提高katG突变对 INH 耐药的程度,导致菌株对 INH 高度耐药。 katG315 联合 AhpC 在准广泛耐药组的突变率显著升高,可能是AhpC突变保持了katG315突变菌株的毒性,使抗结核治疗时间延长,更有利于菌株对其他药物耐药,多个基因联合突变还可能与结核病治疗失败或复发有关[21]

  • 综上所述,katG315 基因突变是本地区 INH 耐药的主要突变位点,且与高度耐药相关,因此临床可通过检测 katG315 基因突变来推测 INH 的耐药性。此外,其他基因(inhA和AhpC)常常与katG315 基因联合突变并且能协同提高INH耐药性,同时还可能合并其他药物耐药,与耐多药、广泛耐药密切相关,临床中需高度警惕这类基因突变。

  • 参考文献

    • [1] WORLD HEALTH ORGANIZATION.Global tuberculo⁃ sis report 2021[R].Geneva:WHO,2021

    • [2] WORLD HEALTH ORGANIZATION.WHO consolidated guidelines on drug ⁃ resistant tuberculosis treatment[R].Geneva:WHO,2019

    • [3] 张海霞,张觅,腾晓燕,等.GeneXpert 法与涂片抗酸染色法检测结核分枝杆菌的比较研究[J].南京医科大学学报(自然科学版),2022,42(1):129-132

    • [4] CHARAN A S,GUPT A N,DIXI T R,et al.Pattern of InhA and KagG mutations inisoniazid monoresistant My⁃ cobacterium tuberculosis isolates[J].Lung India,2020,37(3):227-231

    • [5] ISAKOVA J,SOVKHOZOVA N,VINNIKOV D,et al.Mutations of rpoB,katG,inhA and Ahp genes in rifampi⁃ cin and isoniazid ⁃ resistant Mycobacterium tuberculosis in kyrgyz republic[J].BMC Microbiol,2018,18(1):22

    • [6] MUNIR A,KUMAR N,RAMALINGAM S B,et al.Identi⁃ fication and characterization of genetic determinants of isoniazid and rifampicin resistance in Mycobacterium tu⁃ berculosis in Southern India[J].Sci Rep,2019,9(1):10283

    • [7] 王丹吉,刘巧,陆伟,等.基因芯片技术对耐多药结核病患者治疗的指导价值[J].南京医科大学学报(自然科学版),2018,38(7):983⁃987

    • [8] CASTRO R A D,BORRELL S,GAGNEUX S.The within⁃ host evolution of antimicrobial resistance in Mycobacteri⁃ um tuberculosis[J].FEMS Microbiol Rev,2021,45(4):fuaa071

    • [9] INTURI B,PUJAR G V,PUROHIT M N.Recent advanc⁃ es and structural features of enoyl⁃ACP reductase inhibi⁃ tors of Mycobacterium tuberculosis[J].Arch Pharm Chem Life Sci,2016,349(11):817⁃826

    • [10] PRASAD M S,BHOLE R P,KHEDEKAR P B,et al.My⁃ cobacterium enoyl acyl carrier protein reductase(InhA):a key target for antitubercular drug discovery[J].Bioorg Chem,2021,115:105242

    • [11] UNISSA A N,SELVAKUMAR N,NARAYANAN S,et al.Investigation of Ser315 substitutions within katG Gene in isoniazid ⁃ resistant clinical isolates of Mycobacterium tu⁃ berculosis from south India[J].Biomed Res Int,2015,2015:1-5

    • [12] RUEDA J,REALPE T,MEJIA G I,et al.Genotypic analy⁃ sis of genes associated with independent resistance and cross⁃resistance to isoniazid and ethionamide in Mycobac⁃ terium tuberculosis clinical isolates [J].Antimicrob Agents Chemother,2015,59(12):7805⁃7810

    • [13] MÜLLER B,STREICHER E M,HOEK K G P,et al.InhA promoter mutations:a gateway to extensively drug ⁃ resis⁃ tant tuberculosis in South Africa?[J].Int J Tuberc Lung Dis,2011,15(3):344⁃351

    • [14] PINHATA J M W,BRANDAO A P,DE FREITAS MENDES F,et al.Correlating genetic mutations with iso⁃ niazid phenotypic levels of resistance in Mycobacterium tuberculosis isolates from patients with drug ⁃ resistant tu⁃ berculosis in a high burden setting[J].Eur J Clin Micro⁃biol Infect Dis,2021,40(12):2551-2561

    • [15] SINGH P,JAMAL S,AHMED F,et al.Computational modeling and bioinformatic analyses of functional muta⁃ tions in drug target genes in Mycobacterium tuberculosis [J].Comput Struct Biotechnol J,2021,19:2423⁃2446

    • [16] BAROZI V,MUSYOKA T M,SHEIK AMAMUDDY O,et al.Deciphering isoniazid drug resistance mechanisms on dimeric Mycobacterium tuberculosis KatG via post⁃molecu⁃ lar dynamics analyses including combined dynamic resi⁃ due network metrics[J].ACS Omega,2022,7(15):13313-13332

    • [17] TANIGUCHI K,HAYASHI D,YASUDA N,et al.Compara⁃ tive study of the susceptibility to oxidative stress between two types of Mycobacterium bovis BCG Tokyo 172[J].mSphere,2021,6(2):111-112

    • [18] NOROUZI F,MOGHIM S,FARZANEH S,et al.Signifi⁃ cance of the coexistence of non ⁃ codon 315 katG,inhA,and oxyR⁃ahpC intergenic gene mutations among isoniazid ⁃resistant and multidrug⁃resistant isolates of Mycobacterium tuberculosis:a report of novel mutations[J].Pathog Glob Health,2022,116(1):22-29

    • [19] VERMA H,NAGAR S,VOHRA S,et al.Genome analy⁃ ses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal po⁃ tential drug targets[J].Microb Genom,2021,7(3):000542

    • [20] NIETO R L M,MEHAFFY C,CREISSEN E,et al.Viru⁃ lence of Mycobacterium tuberculosis after acquisition of isoniazid resistance:individual nature of katG mutants and the possible role of AhpC[J].PLoS One,2016,11(11):0166807

    • [21] LIU L G,JIANG F T,CHEN L H,et al.The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non ⁃ 315 in multidrug ⁃ resistant tuberculosis isolates from China[J].Emerg Microbes Infect,2018,7(1):1-10

  • 参考文献

    • [1] WORLD HEALTH ORGANIZATION.Global tuberculo⁃ sis report 2021[R].Geneva:WHO,2021

    • [2] WORLD HEALTH ORGANIZATION.WHO consolidated guidelines on drug ⁃ resistant tuberculosis treatment[R].Geneva:WHO,2019

    • [3] 张海霞,张觅,腾晓燕,等.GeneXpert 法与涂片抗酸染色法检测结核分枝杆菌的比较研究[J].南京医科大学学报(自然科学版),2022,42(1):129-132

    • [4] CHARAN A S,GUPT A N,DIXI T R,et al.Pattern of InhA and KagG mutations inisoniazid monoresistant My⁃ cobacterium tuberculosis isolates[J].Lung India,2020,37(3):227-231

    • [5] ISAKOVA J,SOVKHOZOVA N,VINNIKOV D,et al.Mutations of rpoB,katG,inhA and Ahp genes in rifampi⁃ cin and isoniazid ⁃ resistant Mycobacterium tuberculosis in kyrgyz republic[J].BMC Microbiol,2018,18(1):22

    • [6] MUNIR A,KUMAR N,RAMALINGAM S B,et al.Identi⁃ fication and characterization of genetic determinants of isoniazid and rifampicin resistance in Mycobacterium tu⁃ berculosis in Southern India[J].Sci Rep,2019,9(1):10283

    • [7] 王丹吉,刘巧,陆伟,等.基因芯片技术对耐多药结核病患者治疗的指导价值[J].南京医科大学学报(自然科学版),2018,38(7):983⁃987

    • [8] CASTRO R A D,BORRELL S,GAGNEUX S.The within⁃ host evolution of antimicrobial resistance in Mycobacteri⁃ um tuberculosis[J].FEMS Microbiol Rev,2021,45(4):fuaa071

    • [9] INTURI B,PUJAR G V,PUROHIT M N.Recent advanc⁃ es and structural features of enoyl⁃ACP reductase inhibi⁃ tors of Mycobacterium tuberculosis[J].Arch Pharm Chem Life Sci,2016,349(11):817⁃826

    • [10] PRASAD M S,BHOLE R P,KHEDEKAR P B,et al.My⁃ cobacterium enoyl acyl carrier protein reductase(InhA):a key target for antitubercular drug discovery[J].Bioorg Chem,2021,115:105242

    • [11] UNISSA A N,SELVAKUMAR N,NARAYANAN S,et al.Investigation of Ser315 substitutions within katG Gene in isoniazid ⁃ resistant clinical isolates of Mycobacterium tu⁃ berculosis from south India[J].Biomed Res Int,2015,2015:1-5

    • [12] RUEDA J,REALPE T,MEJIA G I,et al.Genotypic analy⁃ sis of genes associated with independent resistance and cross⁃resistance to isoniazid and ethionamide in Mycobac⁃ terium tuberculosis clinical isolates [J].Antimicrob Agents Chemother,2015,59(12):7805⁃7810

    • [13] MÜLLER B,STREICHER E M,HOEK K G P,et al.InhA promoter mutations:a gateway to extensively drug ⁃ resis⁃ tant tuberculosis in South Africa?[J].Int J Tuberc Lung Dis,2011,15(3):344⁃351

    • [14] PINHATA J M W,BRANDAO A P,DE FREITAS MENDES F,et al.Correlating genetic mutations with iso⁃ niazid phenotypic levels of resistance in Mycobacterium tuberculosis isolates from patients with drug ⁃ resistant tu⁃ berculosis in a high burden setting[J].Eur J Clin Micro⁃biol Infect Dis,2021,40(12):2551-2561

    • [15] SINGH P,JAMAL S,AHMED F,et al.Computational modeling and bioinformatic analyses of functional muta⁃ tions in drug target genes in Mycobacterium tuberculosis [J].Comput Struct Biotechnol J,2021,19:2423⁃2446

    • [16] BAROZI V,MUSYOKA T M,SHEIK AMAMUDDY O,et al.Deciphering isoniazid drug resistance mechanisms on dimeric Mycobacterium tuberculosis KatG via post⁃molecu⁃ lar dynamics analyses including combined dynamic resi⁃ due network metrics[J].ACS Omega,2022,7(15):13313-13332

    • [17] TANIGUCHI K,HAYASHI D,YASUDA N,et al.Compara⁃ tive study of the susceptibility to oxidative stress between two types of Mycobacterium bovis BCG Tokyo 172[J].mSphere,2021,6(2):111-112

    • [18] NOROUZI F,MOGHIM S,FARZANEH S,et al.Signifi⁃ cance of the coexistence of non ⁃ codon 315 katG,inhA,and oxyR⁃ahpC intergenic gene mutations among isoniazid ⁃resistant and multidrug⁃resistant isolates of Mycobacterium tuberculosis:a report of novel mutations[J].Pathog Glob Health,2022,116(1):22-29

    • [19] VERMA H,NAGAR S,VOHRA S,et al.Genome analy⁃ ses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal po⁃ tential drug targets[J].Microb Genom,2021,7(3):000542

    • [20] NIETO R L M,MEHAFFY C,CREISSEN E,et al.Viru⁃ lence of Mycobacterium tuberculosis after acquisition of isoniazid resistance:individual nature of katG mutants and the possible role of AhpC[J].PLoS One,2016,11(11):0166807

    • [21] LIU L G,JIANG F T,CHEN L H,et al.The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non ⁃ 315 in multidrug ⁃ resistant tuberculosis isolates from China[J].Emerg Microbes Infect,2018,7(1):1-10

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