结核病药物治疗的过去、现状及未来  

The past,present and future of tuberculosis treatment

作　　者：毕珂凡 曹丹 丁丞[1] 卢水华 卢洪洲 张广宇 张文宏 李亮[6] 徐凯进[1] 李兰娟[1,2] 张颖 BI Kefan;CAO Dan;DING Cheng;LU Shuihua;LU Hongzhou;ZHANG Guangyu;ZHANG Wenhong;LI Liang;XU Kaijin;LI Lanjuan;ZHANG Ying(The First Affiliated Hospital,Zhejiang University School of Medicine,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,National Clinical Research Center for Infectious Diseases,National Medical Center for Infectious Diseases,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,Hangzhou 310003,China;Jinan Microecological Biomedicine Shandong Laboratory,Jinan 250117,China;Department for Infectious Diseases,Shenzhen Third People’s Hospital,National Clinical Research Center for Infectious Diseases,Shenzhen 518000,Guangdong Province,China;Shulan(Hangzhou)Hospital Affiliated to Shulan International Medical College,Zhejiang Shuren University,Hangzhou 310015,China;Department of Infectious Diseases,Huashan Hospital,Fudan University,National Medical Center for Infectious Diseases,Shanghai 200040,China;Beijing Chest Hospital,Capital Medical University,Beijing 101199,China)

机构地区：[1]浙江大学医学院附属第一医院传染病诊治国家重点实验室国家感染性疾病临床医学研究中心国家传染病医学中心感染性疾病诊治协同创新中心,浙江杭州310003 [2]济南微生态生物医学山东省实验室,山东济南250117 [3]深圳市第三人民医院国家感染性疾病临床医学研究中心,广东深圳518000 [4]浙江树人学院树兰国际医学院附属树兰杭州医院,浙江杭州310015 [5]复旦大学附属华山医院感染科国家传染病医学中心,上海200040 [6]首都医科大学附属北京胸科医院,北京101199

出　　处：《浙江大学学报（医学版）》2022年第6期657-668,共12页Journal of Zhejiang University(Medical Sciences)

基　　金：国家传染病医学中心——张颖启动经费(B2022011-1);济南微生态生物医学山东省实验室课题(JNL-2022050B);国家重点研发计划(2021YFC2301800);国家感染性疾病(结核病)临床医学研究中心项目(2020B1111170014);广东省高水平临床重点专科项目(SZGSP010);上海市市级科技重大专项(HS2021SHZX001);上海市科学技术重大项目(21NL2600100,20dz2260100)。

摘　　要：结核病是一种古老的传染病,在有效药物发现之前结核病的发病率及病死率都非常高。近一百年来陆续发现链霉素、异烟肼、吡嗪酰胺、乙胺丁醇、利福平等一系列经典抗结核化学药物,加上采用不同药物联合使用的治疗方案,有效控制了结核病。随着有效抗结核病药物在临床广泛应用,结核菌基因突变导致的耐多药结核病和广泛耐药结核病在全球蔓延,同时结核菌持留导致的结核病疗程长及复发和潜伏感染也成为临床结核病治疗的瓶颈。异烟肼耐药相关katG突变、利福平耐药相关rpoB突变、吡嗪酰胺耐药相关pncA突变和喹诺酮耐药相关gyrA突变等通过阻滞抗结核前体药物活化、抗生素受酶影响失活、改变药物渗透和药物外排、改变药物靶点等影响抗结核病药物治疗效果;另外,结核菌代谢途径改变、DNA修复系统上调,转录及翻译系统抑制,毒素-抗毒素系统表达和反式翻译蛋白降解等自我修复和保护性机制使结核菌转向非复制性/休眠状态,从而在压力与抗生素治疗环境下存活形成结核菌持留状态。近年来,新型抗结核病药物与新的药物组合治疗方案不断推陈出新,改善了耐多药及广泛耐药结核病的治疗效果并缩短了疗程,但针对结核菌持留尚未有更好的对策。未来需要加强针对耐药及持留结核菌的化学新药和宿主为导向的治疗方法研发、发掘中医药用于结核病治疗的价值等。本文通过回顾结核药物治疗的历史发展和近期进展,特别讨论了结核菌的耐药性和持留性问题,以便为结核治疗未来的发展提供思路。Tuberculosis(TB) is an ancient infectious disease.Before the availability of effective drug therapy,it had high morbidity and mortality.In the past 100 years,the discovery of revolutionary anti-TB drugs such as streptomycin,isoniazid,pyrazinamide,ethambutol and rifampicin,along with drug combination treatment,has greatly improved TB control globally.As anti-TB drugs were widely used,multidrug-resistant(MDR) and extensively drug-resistant(XDR) strains ofMycobacterium tuberculosisemerged due to acquired genetic mutations,and this now presents a major problem for effective treatment.Genes associated with drug resistance have been identified,includingkatGmutations in isoniazid resistance,rpoBmutations in rifampin resistance,pncAmutations in pyrazinamide resistance,andgyrAmutations in quinolone resistance.The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation,drug target alteration,overexpression of drug target,and overexpression of the efflux pump.During the disease process,Mycobacterium tuberculosismay reside in different microenvironments where it is expose to acidic pH,low oxygen,reactive oxygen species and anti-TB drugs,which can facilitate the development of non-replicating persisters and promote bacterial survival.The mechanisms of persister formation may include toxinantitoxin(TA) modules,DNA protection and repair,protein degradation such as transtranslation,efflux,and altered metabolism.In recent years,the use of new anti-TB drugs,repurposed drugs,and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB.The importance of developing more effective drugs targeting persisters ofMycobacterium tuberculosisis emphasized.In addition,host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored.In this article,we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant

关 键 词：结核病 结核分枝杆菌 耐药结核病 诊断 治疗 综述 

分 类 号：R521[医药卫生—内科学]