结核分枝杆菌对德拉马尼耐药及其分子机制研究进展

doi:10.19983/j.issn.2096-8493.20210131

摘要/Abstract

摘要：

结核病是目前全球传染病致死的重要原因,耐药结核分枝杆菌的出现增加了结核病防治的难度,德拉马尼作为抗结核的新药通过抑制结核分枝杆菌细胞壁分枝菌酸合成而发挥杀菌作用,具有很好的耐受性及安全性。然而德拉马尼应用于临床1年便出现了耐药现象。笔者对德拉马尼的临床应用、抗菌机理、药敏实验技术、耐药流行病学调查及耐药分子机制进行综述,以提高临床对德拉马尼的认识,为耐药结核病患者的合理治疗提供更多的参考。

关键词: 分枝杆菌, 结核, 德拉马尼, 微生物敏感性试验, 抗药性, 基因

Abstract:

Tuberculosis (TB) is one of the major causes of death for infectious diseases. The emergence of drug-resistant TB increased the difficulty for TB prevention and control. As a new anti-tuberculosis drug, Delamanid performs its bactericidal action by inhibiting the synthesis of mycolic acid of Mycobacterium tuberculosis cell wall, and has good tolerance and safety. However, within a year of clinical application, drug resistance against Delamanid has already been observed. This paper reviewed the clinical application, antibacterial mechanism, drug susceptibility test technologies, epidemiological investigation and molecular mechanism of drug resistance of Delamanid,in order to promote clinical understanding of Delamanid and provide more reference for rational treatment of drug-resistant tuberculosis patients.

Key words: Mycobacterium, tuberculosis, Delamanid, Microbial sensitivity test, Drug resistance, Gene

中图分类号:

R378.911

周明, 刘皇容, 唐柳生, 刘桑, 刘爱梅. 结核分枝杆菌对德拉马尼耐药及其分子机制研究进展[J]. 结核与肺部疾病杂志, 2022, 3(2): 153-157. doi: 10.19983/j.issn.2096-8493.20210131

ZHOU Ming, LIU Huang-rong, TANG Liu-sheng, LIU Sang, LIU Ai-mei. Research progress on drug resistance of Mycobacterium tuberculosis to Delamanid and its molecular mechanism[J]. Journal of Tuberculosis and Lung Disease, 2022, 3(2): 153-157. doi: 10.19983/j.issn.2096-8493.20210131

图/表 1

表1

德拉马尼的药物敏感性试验方法及MIC浓度

国家,发表年份	药物敏感性试验方法		MIC(mg/L)		菌株类型		菌株数		突变基因		突变类型			参考文献
韩国,2018年	微量肉汤稀释法(BMD)		0.32		XDR-TB/MDR-TB菌株		41		ddn		Gly81Ser,Gly81Asp			[28]
	微量肉汤稀释法(BMD)		≤0.0125		敏感菌株		379		ddn,fbiA		Gly81Ser,Leu113Leu等
瑞士,2020年	微量肉汤稀释法(BMD)		0.015~0.03		未经治疗结核病患者菌株		9		fgd1		Lys270Met,T960C			[29]
	微量肉汤稀释法(BMD)		>8		未经治疗死亡的结核病患者菌株		1		ddn,fgd1		Tyr29del,T960C
意大利,2016年	刃天青微量稀释法(REMA)		0.32		XDR-TB菌株		1		fbiA		Lys-250 STOP			[22]
	刃天青微量稀释法(REMA)		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
意大利,2020年	刃天青微量稀释法(REMA)		0.12~4		TB遗传变异株		74		fbiA,fbiB,fbiC, ddn,fgd1		I208V,Q58Stop, D224N等			[24]
国家,发表年份		药物敏感性试验方法		MIC(mg/L)		菌株类型		菌株数		突变基因		突变类型	参考文献
德国,2019年		刃天青微量稀释法(REMA)		0.25		获得性 delamanid 耐药患者菌株		1		ddn		G53D	[25]
德国,2016年		刃天青微量稀释法(REMA)		≥2.0		MDR-TB菌株		1		fbiA		D49Y,R175H	[39]
		刃天青微量稀释法(REMA)		≤0.016		敏感菌株		1		fbiA		R175H
中国,2017		7H10/7H11琼脂比例法 (APM)		≤0.031		XDR-TB菌株		86		fbiC		val318lle	[27]
		7H10/7H11琼脂比例法 (APM)		一株MIC>0.5,一株MIC>32		XDR-TB菌株		4
美国,2016年		7H10/7H11琼脂比例法 (APM)		0.001~0.05之间, 1株>1,.1株>8		MTB临床分离株		460		-		-	[26]
意大利,2016年		7H10/7H11琼脂比例法 (APM)		0.16		MDR-TB菌株		3		ddn		Trp-88→stop	[22]
		7H10/7H11琼脂比例法 (APM)		0.32		XDR-TB菌株		1		fbiA		Lys-250 STOP
		7H10/7H11琼脂比例法 (APM)		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
瑞士,2015年		MGIT 960液体药敏试验		0.01		MDR-TB菌株		1		fbiA		D49T	[35]
瑞士,2015年		MGIT 960液体药敏试验		0.005~0.04		敏感菌株		12		-		-	[21]
		MGIT 960液体药敏试验		0.32		耐药菌株		3		-		-
意大利,2016年		MGIT 960液体药敏试验		0.16		MDR-TB菌株		3		ddn		Trp-88→stop	[22]
		MGIT 960液体药敏试验		0.125		敏感菌株		108		fbiA,fbiB,fbiC, ddn,fgd1		Ary-72Trp, Glu-83-Asp等
意大利,2018年		微量滴度平板试验UKMYC5		0.06		外部质量评估(EQA)菌株		19		-		-	[30]

表1

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