结核分枝杆菌对德拉马尼的耐药机制研究进展

doi:10.3969/j.issn.1000-6621.2020.11.017

摘要/Abstract

摘要：

当前,由结核分枝杆菌(MTB)引发的结核病仍是全球传染病最主要的死因,耐药菌株的传播给结核病的治疗造成了极大困难。德拉马尼(delamanid,Dlm)作为抗结核新药对耐多药和广泛耐药结核病(MDR-TB/XDR-TB)均有较好的治疗作用,准确并及时地对Dlm耐药菌株进行检测可以最大限度地保证药品临床应用的有效性,提高MDR-TB/XDR-TB的治愈率。MTB获得性耐药多与耐药相关基因突变有关,作者综述了MTB对Dlm耐药的机制及其耐药相关基因突变,为对Dlm耐药菌株进行早期分子诊断提供参考。

关键词: 分枝杆菌,结核, 德拉马尼, 抗药性, 药理作用分子作用机制, 点突变, 综述文献(主题)

Abstract:

At present, tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is still the leading cause of death for infectious diseases worldwide. The spread of drug-resistant strains has caused great difficulties in the treatment of TB. Delamanid (Dlm), a new anti-TB drug, is effective against multi-drug resistant (MDR) or extensively drug-resistant (XDR) tuberculosis. Accurate and timely detection of Dlm-resistant strains can maximize the effectiveness of clinical application for the drug and improve the cure rate of MDR-TB/XDR-TB. The acquired drug resistance in MTB is mainly caused by resistance associated gene mutations. This article reviews the resistance mechanism and resistance associated gene mutations of Dlm, to provide some reference for the early molecular diagnosis of Dlm-resistant strains.

Key words: Mycobacterium tuberculosis, Delamanid, Drug resistance, Molecular mechanisms of pharmacological action, Point mutation, Review literature as topic

刘原园, 初平, 韩书婧, 杨慧, 鲁洁. 结核分枝杆菌对德拉马尼的耐药机制研究进展[J]. 中国防痨杂志, 2020, 42(11): 1237-1242. doi: 10.3969/j.issn.1000-6621.2020.11.017

LIU Yuan-yuan, CHU Ping, HAN Shu-jing, YANG Hui, LU Jie. Research progress for delamanid resistance mechanism of Mycobacterium tuberculosis[J]. Chinese Journal of Antituberculosis, 2020, 42(11): 1237-1242. doi: 10.3969/j.issn.1000-6621.2020.11.017

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突变类型	突变位点	MIC值 (mg/L)	菌株(株)		文献来源
突变类型	突变位点	MIC值 (mg/L)	耐药	敏感	文献来源
非同义突变	Trp88STOP^**	>16	3	0	Schena等^[20]
		>4	2	0	Rancoita等^[24]
	Gly81Asp	>1.6	2	0	Yang等^[18]
	Gly81Ser	>0.4	31	0	Yang等^[18]
	Gly81Ser	<0.0125	0	4	Yang等^[18]
	Gly53Asp	0.25	3	0	Polsfuss等^[25]
	Leu107Pro	1	1	0	Fujiwara等^[15]
	Asn91Thr	>25	2	0	Fujiwara等^[15]
	Arg72Trp	<0.2	0	2	Schena等^[20]
	Glu83Asp	<0.2	0	1	Schena等^[20]
移码突变	434C缺失	>25	1	0	Fujiwara等^[15]
	215G缺失	>25	1	0	Fujiwara等^[15]
	252G—254A缺失	>25	1	0	Fujiwara等^[15]
	59—101缺失	>8	1	0	Fujiwara等^[15]
	91G缺失	≥0.12	1	0	Kardan-Yamchi等^[16]
	329C插入	>25	1	0	Fujiwara等^[15]
同义突变	Gly39Gly	<0.0125	0	5	Yang等^[18]

突变类型	突变位点	MIC值 (mg/L)	菌株(株)		文献来源
突变类型	突变位点	MIC值 (mg/L)	耐药	敏感	文献来源
非同义突变	Gly104Ser	>1	1	0	Ghodousi等^[26]
	Ala89Pro	>25	1	0	Fujiwara等^[15]
	Lys296Glu	<0.2	0	1	Schena等^[20]
	Lys270Met	<0.2	0	12	Schena等^[20]
移码突变	227C缺失	>25	1	0	Fujiwara等^[15]
	630G插入	>25	7	0	Fujiwara等^[15]
	G49fs^*	>0.32	1	0	Bloemberg等^[13]
同义突变	Phe320Phe	>0.2	9	0	Fujiwara等^[15]
		>8	1	0	Wen等^[17]
		<0.2	0	72	Schena等^[20]
	Tyr155Tyr	<0.2	0	3	Schena等^[20]

突变类型	突变位点	MIC值 (mg/L)	菌株(株)		文献来源
突变类型	突变位点	MIC值 (mg/L)	耐药	敏感	文献来源
非同义突变	Lys250STOP^**	>16	1	0	Schena等^[20]
	Asp106Gly	>25	1	0	Fujiwara等^[15]
	Asp49Thr	>0.32	3	0	Bloemberg等^[13]
	Asp49Tyr	≥2	1	0	Hoffmann等^[14]
	Glu249Lys	>16	1	0	Wen等^[17]
	Arg175His	≥2	1	0	Hoffmann等^[14]
		<0.016	0	9	Bloemberg等^[13]
	Gln120Arg	<0.2	0	3	Schena等^[20]
	Thr302Met	<0.2	0	2	Schena等^[20]
	Ala37Asp	<0.0125	0	1	Yang 等^[18]
	His295Tyr	<0.0125	0	1	Yang等^[18]
	Ile220Ser	<0.0125	0	1	Yang等^[18]
移码突变	272—275CAGG插入	>25	1	0	Fujiwara等^[15]
	452A缺失	>25	1	0	Fujiwara等^[15]
	222C, 223C缺失	>25	1	0	Fujiwara等^[15]
同义突变	Glu249Glu	<0.2	0	1	Schena等^[20]
	Pro144Pro	<0.2	0	3	Schena等^[20]
	Leu113Leu	<0.2	0	5	Schena等^[20] 和Yang等^[18]
	Asp63Asp	<0.0125	0	1	Yang等^[18]
	Pro181Pro	0.2	0	1	Yang等^[18]
	Ser194Ser	<0.0125	0	1	Yang等^[18]
	Ser267Ser	<0.0125	0	1	Yang等^[18]

突变类型	突变位点	MIC值 (mg/L)	菌株(株)		文献来源
突变类型	突变位点	MIC值 (mg/L)	耐药	敏感	文献来源
移码突变	1148C—1155G缺失	>0.39	1	0	Fujiwara等^[15]
	1263G—1264G缺失	≥25	1	0	Fujiwara等^[15]
同义突变	Thr92Thr	<0.015	0	1	Polsfuss等^[25]
非同义突变	Leu447Arg	<0.2	0	1	Schena等^[20]
	Lys448Arg	<0.2	0	1	Schena等^[20]
	Phe220Leu	<0.2	0	8	Schena等^[20]

突变类型	突变位点	MIC值 (mg/L)	菌株(株)		文献来源
突变类型	突变位点	MIC值 (mg/L)	耐药	敏感	文献来源
缺失突变	1339G缺失	>25	1	0	Fujiwara等^[15]
	811G,813C缺失	>25	1	0	Fujiwara等^[15]
	699C缺失	>25	1	0	Fujiwara等^[15]
	1638T缺失	>25	1	0	Fujiwara等^[15]
非同义突变	Arg220STOP^**	>25	1	0	Fujiwara等^[15]
	Val318Ile	32	2	0	Pang等^[19]
	Cys98Tyr	>25	1	0	Fujiwara等^[15]
	Leu53Pro	>25	1	0	Fujiwara等^[15]
	Arg536Leu	0.25	2	0	Rancoita等^[24]
	Thr273Ala	<0.2	0	5	Schena等^[20]
	Thr681Ile	<0.2	0	1	Schena等^[20]
同义突变	Leu55Leu	<0.2	0	2	Schena等^[20]
	Leu182Leu	<0.2	0	2	Schena等^[20]
	Asp67Asp	<0.2	0	1	Schena等^[20]
	Leu811Leu	<0.2	0	1	Schena等^[20]