摘要
目的探讨不同抗结核药物对结核分枝杆菌异烟肼耐药相关基因突变的影响,以进一步准确理解结核分枝杆菌异烟肼耐药的分子机制。方法在广州地区分枝杆菌菌株库中选择异烟肼、利福平、乙胺丁醇、链霉素、阿米卡星、克拉霉素、左氧氟沙星、莫西沙星、利福布丁、丙硫异烟胺和对氨基水杨酸等11种抗结核药物的药敏性试验临床测定结果明确的结核分枝杆菌分离株进行katG、mabA-inhA、oxy RahpC、kasA和ndh基因测序,以结核分枝杆菌H37Rv标准序列为参照进行基因突变分析,应用卡方检验对比分析H^(-)(R/F/O)^(-)与H^(-)(R/F/O)^(+)、H^(+)R-与H^(+)R^(+)、H^(+)F^(-)与H^(+)F^(+)和H^(+)O^(-)与H^(+)O^(+)几大菌群之间5种基因突变发生总频率的差异(其中R、H、F、O分别代表利福平、异烟肼、左氧氟沙星与莫西沙星2种氟喹诺酮类药物和其他7种药物,“+”表示耐药、“-”表示敏感)。结果在143株异烟肼敏感结核分枝杆菌株中,H^(-)(R/F/O)-耐药表型株中5种异烟肼耐药相关基因的突变总频率为11.32%(12/106),在37株H^(-)(R/F/O)+耐药表型株中则为40.54%(15/37),两者间差异有统计学意义(χ^(2)=15.289,P<0.001);在224株异烟肼耐药结核分枝杆菌株中,H^(+)R-、H^(+)R^(+)、H^(+)F^(-)、H^(+)F^(+)、H^(+)O^(-)和H^(+)O^(+)六大菌群的突变总频率分别是47.87%(45/94)、93.85%(122/130)、68.64%(116/169)、89.09%(49/55)、55.56%(15/27)和77.16%(152/197),H^(+)R-与H^(+)R^(+)、H^(+)F^(-)与H^(+)F^(+)和H^(+)O^(-)与H^(+)O^(+)之间基因突变总频率差异有统计学意义(χ^(2)=60.778、11.99、5.841,P<0.001、0.001和0.016)。结论结核分枝杆菌INH耐药相关基因突变虽然取决于对INH的敏感性,但是否同时对其他抗结核药物耐药也可产生重要影响,值得人们深入研究。
Objective To study the effects of resistance to other anti-tuberculosis drugs on mutations of isoniazid resistance related genes in M.tuberculosis for further accurately understanding the molecular mechanism of isoniazid resistance in M.tuberculosis.Methods The M.tuberculosis isolates which have complete drug sensitivity test(DST)data of eleven kinds of anti-tuberculosis drugs(isoniazid,rifampicin,ethambutol,streptomycin,amika-cin,clarithromycin,levofloxacin,moxifloxacin,rifambdin,propylthioisonicotinamide and p-aminosalicylic acid)were were sampled from the bio-bank of Mycobacteria in Guangzhou.Then their katG,mabA-inhA,oxyR-ahpC,kasA and ndh genes were sequenced,and gene mutations were analyzed by comparing with the sequences of these genes of M.tuberculosis reference strain H37Rv.Statistical comparative analysis of the total gene mutation frequen-cies of five genes between bacterial florae of H(-R/F/O)-and H(-R/F/O)^(+),H^(+)R^(-) and H^(+)R^(+),H^(+)F^(-)and H^(+)F^(+),and H^(+)O^(-)and H^(+)O^(+)resistant phenotypes were performed by using Chi-square test(Among them,“R”,“H”,“F”,“O”,“+”and“-”represent rifampicin,isoniazid,Levofloxacin or moxifloxacin and seven kinds of other drugs,drugresistance and drug-susceptibility respectively.Results The first,the total gene mutation frequency of five genes in M.tuberculosis strains with H^(-)(R/F/O)-was 11.32%(12/106)while the frequency was 40.54%(15/37)in M.tuberculosis strains with H^(-)(R/F/O)+among 143 isoniazid-sensitive mycobacterium tuberculosis strains,which there was significant differences between them(χ^(2)=15.289,P˂0.001).The second,the total gene mutation frequency of five genes in M.tuberculosis strains with H^(+)R-,H^(+)R^(+),H^(+)F^(-),H^(+)F^(+),H^(+)O^(-)and H^(+)O^(+)were 47.87%(45/94),93.85%(122/130),68.64%(116/169),89.09%(49/55),55.56%(15/27)and 77.16%(152/197).There were significant differences between M.tuberculosis strains with H^(+)R-and H^(+)R^(+),H^(+)F^(-)and H^(+)F^(+),H^(+)O^(-)and H^(+)O^(+)based on their chi-square values of 60.778,11.99 and 5.841 and P values of˂0.001,0.001 and 0.016,respectively.Conclusions It is essential that important effects on isoniazid resistance related genes mutations in M.tuberculosis from other anti-tuberculosis drugs resistance should be studied extensively and deeply although these mutations were usually decided by their sensitivity to isoniazid.
作者
龚兰
牛群
王楠
雷杰
吴玲
邓丽
谢贝
王琪
李华
杨瑜
刘志辉
孟繁荣
GONG Lan;NIU Qun;WANG Nan;LEI Jie;WU Ling;DENG Li;XIE Bei;WANG Qi;LI Hua;YANG Yu;LIU Zhihui;MENG Fanrong(Institute of Pulmonary Diseases,Guangzhou Chest Hospital,Guangzhou 510095,China;State Key Laboratory of Respiratory Diseases,Guangzhou 510182,China;不详)
出处
《实用医学杂志》
CAS
北大核心
2023年第11期1353-1358,共6页
The Journal of Practical Medicine
基金
国家重点研发计划“病原学与防疫技术体系研究”重点专项(编号:2022YFC2304800)
广东省自然科学基金项目(编号:2018A030313550)
广州市科技计划项目(编号:202002030152)
广州市医学重点学科(2021-2023)结核病学。
关键词
结核分枝杆菌
异烟肼
基因突变
Mycobacterium tuberculosis
Isoniazid
gene mutation
