一种基于Nanopore测序仪进行结核分枝杆菌耐药检测分析系统及其构建方法与流程

一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统及其构建方法
技术领域
1.本发明涉及基因检测分析领域，特别是一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统及其构建方法。


背景技术：

2.nanopore测序是一种单分子、实时测序的新一代测序方法，其以单分子dna（rna）通过生物纳米孔的电流变化推测碱基组成而进行测序。nanopore测序具有长度长、实时测序、按需测序以及灵活、可扩展等特点。与传统测序技术不同的是，用户可以自行掌握测序时间、地点、以及需要使用的芯片数量，这意味着用户可以根据样本的数量选择芯片数量，随数据量要求随时启动和停止实验。
3.结核分枝杆菌是结核病的病原体，随着抗结核药物的不断发展和居民卫生状况的改善，结核病的发病率和病死率曾大幅度下降。但自20世纪80年代以来，由于结核分枝杆菌耐药菌株，尤其是耐多药菌株的产生和传播，肺结核的发病率又有所提升，是导致人类死亡的重要疾病之一。要使肺结核发病率和病死率降低，必须实行结核病的早期诊断及其耐药性检测。采用传统的结核分枝杆菌分离培养和药敏试验通常需要1
‑
2月时间，显然不能满足临床开展有效治疗的需要。因此，阐明结核分枝杆菌耐药机制，建立快速检测耐药结核分枝杆菌的诊断试验，已成为当前结核病研究的重要课题。
4.现有的结核分枝杆菌耐药检测方法耗时长，且灵敏度和特异性低，本发明解决这样的问题，具有广泛应用于临床的潜力。


技术实现要素：

5.为解决现有技术的不足，本发明的目的在于提供一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统及其构建方法，本发明能够快速、准确鉴定病原微生物和检测结核分枝杆菌耐药性质。
6.为了达到上述目的，本发明采用如下技术方案：一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统，包括：微生物序列参考库模块，菌株耐药参考库模块，病原微生物鉴定模块，突变检测模块和耐药数据库注释模块；微生物序列参考库模块为通过多个数据库的微生物rrna序列构建微生物序列参考库，对序列进行过滤，形成高可信度的微生物序列参考库；病原微生物鉴定模块包括：测序数据样品拆分模块，数据质控处理模块，比对分析模块和物种分类模块。
7.测序数据样品拆分模块为：通过guppy软件将由测序仪产生的fast5格式文件转换成fastq格式，每个样品都具有独特的barcode序列，每条序列的前一段序列就是barcode序列，将这段序列与测序仪提供的barcode序列库进行比对，将比对分数大于80的序列视为可
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isoniazid katg
ꢀꢀꢀꢀꢀ
y229f
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n138s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n138disoniazid katg
ꢀꢀꢀꢀꢀ
h108q
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h108e
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w107risoniazid katg
ꢀꢀꢀꢀꢀ
r104l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g33v
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g111s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h417qisoniazid katg
ꢀꢀꢀꢀꢀ
e607a
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q461p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g125s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n508disoniazid katg
ꢀꢀꢀꢀꢀ
l147p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n660d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a312p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s383p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h97r
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r489s
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m420tisoniazid katg
ꢀꢀꢀꢀꢀ
d387hisoniazid katg
ꢀꢀꢀꢀꢀ
g123e
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g299s
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d419hisoniazid katg
ꢀꢀꢀꢀꢀ
m176tisoniazid katg
ꢀꢀꢀꢀꢀ
r632c
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d542h
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y64s
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y95c
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
p131t
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a139p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d142gisoniazid katg
ꢀꢀꢀꢀꢀ
a162visoniazid katg
ꢀꢀꢀꢀꢀ
g269disoniazid katg
ꢀꢀꢀꢀꢀ
t306p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r385wisoniazid katg
ꢀꢀꢀꢀꢀ
d387gisoniazid katg
ꢀꢀꢀꢀꢀ
t394misoniazid katg
ꢀꢀꢀꢀꢀ
q439p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
f483l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a541disoniazid katg
ꢀꢀꢀꢀꢀ
g32d
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v47e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d194gisoniazid katg
ꢀꢀꢀꢀꢀ
a256t
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
t667p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m624v
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a717p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
i335t
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q127p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q352e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y98c
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a379t
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g269risoniazid katg
ꢀꢀꢀꢀꢀ
a431v
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d194yisoniazid katg
ꢀꢀꢀꢀꢀ
s17t
ꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a93t
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d36e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a110visoniazid katg
ꢀꢀꢀꢀꢀ
a139visoniazid katg
ꢀꢀꢀꢀꢀ
g300w isoniazid katg
ꢀꢀꢀꢀꢀ
h276m
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q295hisoniazid katg
ꢀꢀꢀꢀꢀ
s17n
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g19d
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q224e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a243s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a550disoniazid katg
ꢀꢀꢀꢀꢀ
s140n
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g279d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g285disoniazid katg
ꢀꢀꢀꢀꢀ
g316disoniazid katg
ꢀꢀꢀꢀꢀ
s457i
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g593d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d63e
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n133t
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
p232s
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q127e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
i317v
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315r
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315t
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315n
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w191risoniazid katg
ꢀꢀꢀꢀꢀ
t667p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v469l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r463l
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d735nisoniazid katg
ꢀꢀꢀꢀꢀ
g629s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l587misoniazid katg
ꢀꢀꢀꢀꢀ
s315t
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315r
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315g
ꢀꢀꢀ
isoniazid pnca
ꢀꢀꢀꢀ
d63g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q10k
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t47s
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49v
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s66p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
k96e
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a102t
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a102vpyrazinamide pnca
ꢀꢀꢀꢀ
l116r
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v125dpyrazinamide pnca
ꢀꢀꢀꢀ
i133t
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q141p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
r154gpyrazinamide pnca
ꢀꢀꢀꢀ
t160p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a161p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12a
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12n
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h51q
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a171p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
h57d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68l
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139apyrazinamide pnca
ꢀꢀꢀꢀ
r121p
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h137rpyrazinamide pnca
ꢀꢀꢀꢀ
w119rpyrazinamide pnca
ꢀꢀꢀꢀ
f94p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
t76p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l19p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s104c
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
i90s
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c14r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c14y
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g23v
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
v45g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a46e
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49a
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
f58l
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y68d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s67p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
w68g
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68s
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t76i
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g78d
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l85r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
k96q
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y103hpyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
y103s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t135p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d136npyrazinamide pnca
ꢀꢀꢀꢀ
d136y
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139mpyrazinamide pnca
ꢀꢀꢀꢀ
a146t
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v155gpyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
l159r
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l172p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v180f
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l172a
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a171t
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h51y
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p62h
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
a171vpyrazinamide pnca
ꢀꢀꢀꢀ
d136hpyrazinamide pnca
ꢀꢀꢀꢀ
l27p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p54l
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c72w
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
m175vpyrazinamide pnca
ꢀꢀꢀꢀ
h59d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
a46v
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d53a
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h71e
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h82r
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g97s
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a134vpyrazinamide pnca
ꢀꢀꢀꢀ
c138s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
t168n
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t47p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a121p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y34s
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g17d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p54t
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a140s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
t47a
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12e
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68c
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t142m
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t142k
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139l
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c138ypyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
h137p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g132s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
n118t
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
k96n
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l85p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c72r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p69r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
y41h
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a26g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y34d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49n
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h51r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p54l
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
h57d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h57r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
f58s
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p62s
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s67p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68g
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
p69r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h71r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t76p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h82r
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l85r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g97s
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t100p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
q10p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q10r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l116r
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12a
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v128gpyrazinamide pnca
ꢀꢀꢀꢀ
i133t
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t135p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
d136ypyrazinamide pnca
ꢀꢀꢀꢀ
c14r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c138r
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139g
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q141p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a146e
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a146vpyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
l151s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
m175vpyrazinamide pnca
ꢀꢀꢀꢀ
v180f
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v180a
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v180gpyrazinamide pnca
ꢀꢀꢀꢀ
l182s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l182s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
e174g
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l72p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a161gpyrazinamide pnca
ꢀꢀꢀꢀ
v157g
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
r157wpyrazinamide pnca
ꢀꢀꢀꢀ
t100p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
r140gpyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
c138wpyrazinamide pnca
ꢀꢀꢀꢀ
k96m
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s164p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h57q
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g17s
ꢀꢀꢀꢀꢀ
pyrazinamide rpob
ꢀꢀꢀꢀꢀ
s531l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
n518t
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s522q
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
k527nrifampicin rpob
ꢀꢀꢀ
r528hrifampicin rpob
ꢀꢀꢀ
s512r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l521m
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526grifampicin rpob
ꢀꢀꢀ
f505l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s574l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
g507s
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
g507drifampicin rpob
ꢀꢀꢀ
t508p
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
t508a
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
t508h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513drifampicin rpob
ꢀꢀꢀ
q513e
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s456wrifampicin rpob
ꢀꢀꢀ
d516h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
n519krifampicin rpob
ꢀꢀꢀ
g523arifampicin rpob
ꢀꢀꢀ
h526f
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526q
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s531f
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s531c
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512t
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511r
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512i
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526nrifampicin rpob
ꢀꢀꢀ
r529qrifampicin rpob
ꢀꢀꢀ
h526t
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
r528p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l524s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q517l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s509q
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s509r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
e672d
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526e
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511v
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l533p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516vrifampicin rpob
ꢀꢀꢀ
t508n
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512n
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
p520t
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s531wrifampicin rpob
ꢀꢀꢀ
s531g
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526d
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
k527qrifampicin rpob
ꢀꢀꢀ
d516t
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516y
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
m515i
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
m515vrifampicin rpob
ꢀꢀꢀ
l511p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i572f
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s522l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526yrifampicin rpob
ꢀꢀꢀ
l538r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
v176f
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q438krifampicin rpob
ꢀꢀꢀ
l533r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d441vrifampicin rpob
ꢀꢀꢀ
d441y
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s447q
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h451yrifampicin rpob
ꢀꢀꢀ
h451crifampicin rpob
ꢀꢀꢀ
h451d
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h451rrifampicin rpob
ꢀꢀꢀ
s456l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526crifampicin rpob
ꢀꢀꢀ
e250g
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i1106trifampicin rpob
ꢀꢀꢀ
q975hrifampicin rpob
ꢀꢀꢀ
g836s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516grifampicin rpob
ꢀꢀꢀ
d516nrifampicin rpob
ꢀꢀꢀ
q513k
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h835rrifampicin rpob
ꢀꢀꢀ
r827hrifampicin rpob
ꢀꢀꢀ
l731p
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
f503s
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i480v
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l452p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
p45l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450wrifampicin rpob
ꢀꢀꢀ
p45s
ꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445rrifampicin rpob
ꢀꢀꢀ
h445y
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d435vrifampicin rpob
ꢀꢀꢀ
d435grifampicin rpob
ꢀꢀꢀ
d435yrifampicin rpob
ꢀꢀꢀ
m434i
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q432p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l430p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445drifampicin rpob
ꢀꢀꢀ
h445yrifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
v146f
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
a381vrifampicin rpob
ꢀꢀꢀ
l521p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526rrifampicin rpob
ꢀꢀꢀ
s522w
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q490hrifampicin rpob
ꢀꢀꢀ
e504a
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d518h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513rrifampicin rpob
ꢀꢀꢀ
h526p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q517hrifampicin rpob
ꢀꢀꢀ
t508s
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511mrifampicin rpob
ꢀꢀꢀ
d516krifampicin rpob
ꢀꢀꢀ
n518hrifampicin rpob
ꢀꢀꢀ
n518i
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l538p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l545mrifampicin rpob
ꢀꢀꢀ
l571v
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
r633c
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin gidb
ꢀꢀꢀ
n52t
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
i55s
ꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
d67h
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
e92a
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l79s
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
s70r
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g71v
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
q127p
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a138e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a183t
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
l79f
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g117e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
r47q
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
w45c
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l49f
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g164cstreptomycin gidb
ꢀꢀꢀꢀꢀ
p84c
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
v188mstreptomycin gidb
ꢀꢀꢀꢀꢀ
a134e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
p75s
ꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v124g
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a183e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v188gstreptomycin gidb
ꢀꢀꢀꢀꢀ
g37v
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
a200e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v139astreptomycin gidb
ꢀꢀꢀꢀꢀ
p84l
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g30r
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
h48y
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l79s
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
w148rstreptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
w45s
ꢀꢀꢀꢀ
streptomycin。
12.一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统的构建方法，步骤一，构建用于nanopore测序数据比对的微生物序列参考库：利用多个数据库的微生物rrna序列，构建微生物序列参考库，对序列进行过滤得到高可信度的微生物序列参考库；步骤二，测序待测样品，将测序reads比对到微生物序列参考库并鉴定病原微生物，病原微生物鉴定通过测序数据样品拆分、数据质控处理、比对分析和物种分类对测序数据进行分析；测序数据样品拆分的方法具体包括如下步骤：通过guppy软件将由测序仪产生的fast5格式文件转换成fastq格式，找到样品的barcode序列，将这段序列与测序仪提供的barcode序列库进行比对，将比对分数大于80的序列视为可信的分配；barcode序列指：每个样品都具有独特的barcode序列，每条序列的前一段序列就是barcode序列；数据质控处理的方法为：采用nanofilt软件进行质控，每条序列都有一个平均测序数据质量值q，q值小于7的序列为不合格序列；比对分析的方法为：将质控处理后的序列采用minimap2进行快速比对，计算reads 的identity和coverage，筛选identity 大于90%且coverage大于85%作为比对质量高的结果；物种分类的方法为：将序列与微生物序列参考库进行比对，选择比对分数最高、identity大于90%且coverage大于85%的记录作为该序列的最佳比对记录；然后将最佳比对记录id与物种谱系数据库进行匹配，获取物种分类结果；步骤三，将来源于菌株的序列比对到菌株参考基因组并鉴定基因突变：
将来源于菌株样品序列采用minimap2比对到菌株参考基因组，获得bam文件；利用samtools对bam文件进行排序，使用samtools mpileup提取mpileup文件，再使用varscan2对mpileup文件进行处理，获得突变结果并以vcf格式保存，然后使用snpeff对突变结果进行基因注释；步骤四，以card数据库结合文献报道的菌株耐药位点信息整合成自建菌株耐药参考库；步骤五，将基因突变位点与耐药数据库中的突变位点进行匹配关联，获取基因突变位点对应的耐药药物名称。
13.采用上述技术方案后，本发明的有益之处在于：本发明基于nanopore测序仪独特开发，整个工作流程的周转时间能够达到小于12小时，测序速度比其他测序仪更快；且测序reads读长更长，nanopore测序reads读长可达到2m；本发明能够快速、准确鉴定病原微生物和检测结核分枝杆菌耐药性质，灵敏度为95%、特异性为96%；本发明构建微生物序列参考库以及结核分枝杆菌耐药参考库，为其他分析系统的构建提供了理论基础，具有广泛的应用前景；本发明给检测菌株耐药性质提供应用基础，具有广泛的应用前景。
附图说明
14.图1为本发明构建方法的一种实施例的流程图。
具体实施方式
15.以下结合附图和具体实施例对本发明作具体的介绍。
16.一种基于nanopore测序仪进行结核分枝杆菌耐药检测分析系统的构建方法，步骤一，构建用于nanopore测序数据比对的微生物序列参考库：利用多个数据库的微生物rrna序列，构建微生物序列参考库，对序列进行过滤得到高可信度的微生物序列参考库；作为一种优选，微生物序列参考库模块中的多个数据库包括：ncbi 16s rrna、18s rrna、its 、silva和unite数据库。这些数据库是目前公开发表的较为全面的数据库，不易造成微生物漏检，需要说明的是：数据库的选取不受限制，在未来若出现更加全面的数据库也可以进行替换。
17.步骤二，测序待测样品，将测序reads比对到微生物序列参考库并鉴定病原微生物，病原微生物鉴定通过测序数据样品拆分、数据质控处理、比对分析和物种分类对测序数据进行分析；测序数据样品拆分的方法具体包括如下步骤：通过guppy软件将由测序仪产生的fast5格式文件转换成fastq格式，找到样品的barcode序列，将这段序列与测序仪提供的barcode序列库进行比对，将比对分数大于80的序列视为可信的分配；barcode序列指：每个样品都具有独特的barcode序列，每条序列的前一段序列就
是barcode序列；数据质控处理的方法为：采用nanofilt软件进行质控，每条序列都有一个平均测序数据质量值q，q值小于7的序列为不合格序列；比对分析的方法为：将质控处理后的序列采用minimap2进行快速比对，计算reads 的identity和coverage，筛选identity 大于90%且coverage大于85%作为比对质量高的结果；作为一种实施例，计算reads 的identity和coverage的方法为：minimap2比对结果中第13列含有前缀de:f:，该列值加上identity等于1；minimap2比对结果第2列代表序列长度，第3列代表比对其实位置，第4列代表比对终止位置，将第4列与第3列的差值除以第2列等于coverage。需要说明的是：这只是一种优选实施例，只要能计算reads 的identity和coverage的方法都适用于本发明。
18.物种分类的方法为：将序列与微生物序列参考库进行比对，选择比对分数最高、identity大于90%且coverage大于85%的记录作为该序列的最佳比对记录；然后将最佳比对记录id与物种谱系数据库进行匹配，获取物种分类结果；步骤三，将来源于菌株的序列比对到菌株参考基因组并鉴定基因突变：将来源于菌株样品序列采用minimap2比对到菌株参考基因组，获得bam文件；利用samtools对bam文件进行排序，使用samtools mpileup提取mpileup文件，再使用varscan2对mpileup文件进行处理，获得突变结果并以vcf格式保存，然后使用snpeff对突变结果进行基因注释；菌株参考基因组为结核分枝杆菌株参考基因组，结核分枝杆菌株参考基因组为mycobacterium tuberculosis h37rv，ncbi登录号为nc_000962.3。
19.步骤四，以card数据库结合文献报道的菌株耐药位点信息整合成自建菌株耐药参考库；自建菌株耐药参考库为自建结核分枝杆菌耐药参考库，自建结核分枝杆菌耐药参考库包括如下内容：gene mutation drug ahpc c
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‑
8c
ꢀꢀꢀꢀꢀꢀ
isoniazid inha
ꢀꢀꢀꢀꢀꢀꢀ
t
‑
8a
ꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r418l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w328fisoniazid katg
ꢀꢀꢀꢀꢀ
w321fisoniazid katg
ꢀꢀꢀꢀꢀ
t275v
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m255yisoniazid katg
ꢀꢀꢀꢀꢀ
m255i
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m255cisoniazid katg
ꢀꢀꢀꢀꢀ
w107f
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473nisoniazid katg
ꢀꢀꢀꢀꢀ
v473gisoniazid katg
ꢀꢀꢀꢀꢀ
v473yisoniazid katg
ꢀꢀꢀꢀꢀ
v473w
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473f
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473misoniazid katg
ꢀꢀꢀꢀꢀ
v473r
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473kisoniazid katg
ꢀꢀꢀꢀꢀ
v473i
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v473disoniazid katg
ꢀꢀꢀꢀꢀ
l472i
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l472q
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l472k
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q471hisoniazid katg
ꢀꢀꢀꢀꢀ
q471y
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l436g
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
t435r
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l430v
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
l427i
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d311s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d311nisoniazid katg
ꢀꢀꢀꢀꢀ
s303c
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s303l
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315i
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m126i
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s315n
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a234g
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v68g
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
p131q
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r128qisoniazid katg
ꢀꢀꢀꢀꢀ
l101p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r463l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w91r
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
p131r
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a350s
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y337cisoniazid katg
ꢀꢀꢀꢀꢀ
w328g isoniazid katg
ꢀꢀꢀꢀꢀ
t275p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
t262r
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w300g isoniazid katg
ꢀꢀꢀꢀꢀ
y229f
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n138s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n138d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h108qisoniazid katg
ꢀꢀꢀꢀꢀ
h108e
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
w107risoniazid katg
ꢀꢀꢀꢀꢀ
r104l
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g33v
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g111s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h417qisoniazid katg
ꢀꢀꢀꢀꢀ
e607a
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q461p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g125s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n508disoniazid katg
ꢀꢀꢀꢀꢀ
l147p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
n660disoniazid katg
ꢀꢀꢀꢀꢀ
a312p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
s383p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h97r
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r489s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m420tisoniazid katg
ꢀꢀꢀꢀꢀ
d387hisoniazid katg
ꢀꢀꢀꢀꢀ
g123e
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g299s
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d419hisoniazid katg
ꢀꢀꢀꢀꢀ
m176tisoniazid katg
ꢀꢀꢀꢀꢀ
r632c
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d542hisoniazid katg
ꢀꢀꢀꢀꢀ
y64s
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y95c
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
p131t
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a139p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d142gisoniazid katg
ꢀꢀꢀꢀꢀ
a162visoniazid katg
ꢀꢀꢀꢀꢀ
g269d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
t306p
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
r385wisoniazid katg
ꢀꢀꢀꢀꢀ
d387gisoniazid katg
ꢀꢀꢀꢀꢀ
t394m
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q439p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
f483l
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a541disoniazid katg
ꢀꢀꢀꢀꢀ
g32d
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
v47e
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d194gisoniazid katg
ꢀꢀꢀꢀꢀ
a256t
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
t667p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
m624visoniazid katg
ꢀꢀꢀꢀꢀ
a717p
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
i335t
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q127p
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
q352e
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
y98c
ꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a379t
ꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
g269r
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a431visoniazid katg
ꢀꢀꢀꢀꢀ
d194yisoniazid katg
ꢀꢀꢀꢀꢀ
s17t
ꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a93t
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
d36e
ꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
a110visoniazid katg
ꢀꢀꢀꢀꢀ
a139visoniazid katg
ꢀꢀꢀꢀꢀ
g300w
ꢀꢀꢀꢀꢀꢀꢀ
isoniazid katg
ꢀꢀꢀꢀꢀ
h276misoniazid katg
ꢀꢀꢀꢀꢀ
q295hisoniazid katg
ꢀꢀꢀꢀꢀ
s17n
ꢀꢀꢀꢀꢀ
pnca
ꢀꢀꢀꢀ
g97s
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a134vpyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
c138s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t168n
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t47p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a121p
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y34s
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g17d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p54t
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
a140s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t47a
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12e
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68c
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t142mpyrazinamide pnca
ꢀꢀꢀꢀ
t142k
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139l
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
c138ypyrazinamide pnca
ꢀꢀꢀꢀ
h137p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g132s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
n118t
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
k96n
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l85p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c72r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
p69r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y41h
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a26g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
y34d
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49n
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d49g
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h51r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
p54l
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h57d
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h57r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
f58s
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p62s
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s67p
ꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
w68r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
w68g
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
p69r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h71r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
t76p
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h82r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l85r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g97s
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
t100p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q10p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
q10r
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l116r
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d12a
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v128gpyrazinamide pnca
ꢀꢀꢀꢀ
i133t
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
t135p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
d136ypyrazinamide pnca
ꢀꢀꢀꢀ
c14r
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
c138r
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v139gpyrazinamide pnca
ꢀꢀꢀꢀ
q141p
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a146e
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
a146vpyrazinamide pnca
ꢀꢀꢀꢀ
l151s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
m175vpyrazinamide pnca
ꢀꢀꢀꢀ
v180f
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v180apyrazinamide pnca
ꢀꢀꢀꢀ
v180gpyrazinamide pnca
ꢀꢀꢀꢀ
l182s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
l182s
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
e174g
ꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
l72p
ꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
a161g
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
v157gpyrazinamide pnca
ꢀꢀꢀꢀ
r157wpyrazinamide pnca
ꢀꢀꢀꢀ
t100p
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀꢀꢀꢀ
r140gpyrazinamide pnca
ꢀꢀꢀꢀ
c138wpyrazinamide pnca
ꢀꢀꢀꢀ
k96m
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
s164p
ꢀꢀꢀꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
h57q
ꢀꢀꢀꢀ
pyrazinamide pnca
ꢀꢀꢀꢀ
g17s
ꢀꢀꢀꢀꢀ
pyrazinamide rpob
ꢀꢀꢀꢀꢀ
s531l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀꢀꢀꢀꢀ
n518t
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s522q
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
k527nrifampicin rpob
ꢀꢀꢀ
r528hrifampicin rpob
ꢀꢀꢀ
s512r
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l521mrifampicin rpob
ꢀꢀꢀ
h526grifampicin rpob
ꢀꢀꢀ
f505l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s574l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
g507s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
g507drifampicin rpob
ꢀꢀꢀ
t508p
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
t508a
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
t508h
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513drifampicin rpob
ꢀꢀꢀ
q513e
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s456w
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516hrifampicin rpob
ꢀꢀꢀ
n519krifampicin rpob
ꢀꢀꢀ
g523arifampicin rpob
ꢀꢀꢀ
h526f
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526q
rifampicin rpob
ꢀꢀꢀ
s531f
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s531c
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512t
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512i
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526nrifampicin rpob
ꢀꢀꢀ
r529q
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526t
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
r528p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l524s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q517l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s509q
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s509r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
e672d
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526e
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511v
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l533p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516vrifampicin rpob
ꢀꢀꢀ
t508n
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s512n
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
p520t
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s531wrifampicin rpob
ꢀꢀꢀ
s531g
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526drifampicin rpob
ꢀꢀꢀ
h526s
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
k527qrifampicin rpob
ꢀꢀꢀ
d516t
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516yrifampicin rpob
ꢀꢀꢀ
m515i
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
m515vrifampicin rpob
ꢀꢀꢀ
l511p
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i572f
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s522l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526yrifampicin rpob
ꢀꢀꢀ
l538r
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
v176f
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q438krifampicin rpob
ꢀꢀꢀ
l533r
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d441v
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d441yrifampicin rpob
ꢀꢀꢀ
s447q
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h451yrifampicin rpob
ꢀꢀꢀ
h451c
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h451drifampicin rpob
ꢀꢀꢀ
h451rrifampicin rpob
ꢀꢀꢀ
s456l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526c
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
e250g
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i1106trifampicin rpob
ꢀꢀꢀ
q975hrifampicin rpob
ꢀꢀꢀ
g836s
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d516grifampicin rpob
ꢀꢀꢀ
d516n
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q513krifampicin rpob
ꢀꢀꢀ
q513l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h835rrifampicin rpob
ꢀꢀꢀ
r827h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l731p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
f503s
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
i480v
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l452p
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
p45l
ꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450wrifampicin rpob
ꢀꢀꢀ
p45s
ꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445r
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445yrifampicin rpob
ꢀꢀꢀ
d435vrifampicin rpob
ꢀꢀꢀ
d435grifampicin rpob
ꢀꢀꢀ
d435y
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
m434i
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q432p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l430p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445l
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h445drifampicin rpob
ꢀꢀꢀ
h445yrifampicin rpob
ꢀꢀꢀ
s450l
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
v146f
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
a381vrifampicin rpob
ꢀꢀꢀ
l521p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
h526r
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
s522wrifampicin rpob
ꢀꢀꢀ
q513p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q490hrifampicin rpob
ꢀꢀꢀ
e504a
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
d518hrifampicin rpob
ꢀꢀꢀ
q513rrifampicin rpob
ꢀꢀꢀ
h526p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
q517h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
t508s
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l511mrifampicin rpob
ꢀꢀꢀ
d516krifampicin rpob
ꢀꢀꢀ
n518h
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
n518i
ꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l538p
ꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
l545mrifampicin rpob
ꢀꢀꢀ
l571v
ꢀꢀꢀꢀꢀꢀꢀ
rifampicin rpob
ꢀꢀꢀ
r633c
ꢀꢀꢀ
rifampicin gidb
ꢀꢀꢀ
n52t
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
i55s
ꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
d67h
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
e92a
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l79s
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
s70r
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
g71v
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
q127p
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a138e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a183t
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l79f
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g117e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
r47q
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
w45c
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l49f
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
g164cstreptomycin gidb
ꢀꢀꢀꢀꢀ
p84c
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v188mstreptomycin gidb
ꢀꢀꢀꢀꢀ
a134e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
p75s
ꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
v124gstreptomycin gidb
ꢀꢀꢀꢀꢀ
a183e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v188gstreptomycin gidb
ꢀꢀꢀꢀꢀ
g37v
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
a200e
ꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
v139astreptomycin gidb
ꢀꢀꢀꢀꢀ
p84l
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀꢀꢀ
g30r
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
h48y
ꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
l79s
ꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
w148r
ꢀꢀꢀꢀꢀꢀꢀ
streptomycin gidb
ꢀꢀꢀꢀꢀ
w45s
ꢀꢀꢀꢀ
streptomycin。
20.步骤五，将基因突变位点与耐药数据库中的突变位点进行匹配关联，获取基因突变位点对应的耐药药物名称。
21.需要说明的是：本发明的耐药分析系统逻辑同样也适合于其他菌株的突变相关的耐药分析。
22.以下用本发明构建成的结核分枝杆菌耐药检测分析系统进行效果验证：为了验证本发明的结果和优点，申请人收集了676个临床已知结核耐药信息（四个药物利福平、异烟肼、链霉素、乙胺丁醇）的样本，利用本发明进行结核耐药分析。结果发现，本发明针对4中结核药物耐药检测的灵敏度和特异性结果如下表1所示，抗结核药物临界浓度如表2所示。
23.表1结核耐药分析检测结果统计 rifampin利福平isoniazid异烟肼streptomycin链霉素ethambutol乙胺丁醇totaltp真阳性61562622165tn真阴性132125115113485fp假阳性465318fn假阴性23218total199190148139676sensitivity=tp/(tp fn)，灵敏度97����%specificity=tn/(tn fp)，特异性97����%
表2抗结核药物临界浓度抗结核药物mic值范围（μg/ml）临界浓度（μg/ml）利福平0.12
‑
161异烟肼0.03
‑
40.2链霉素0.25
‑
322乙胺丁醇0.5
‑
325由表1可知：本结核分歧杆菌耐药检测分析系统能够快速、准确鉴定病原微生物和检测结核分枝杆菌耐药性质，总的灵敏度为95%、特异性为96%。
24.药物敏感性检测：采用微孔板药敏检测法测定最小抑菌浓度（mic），将配制好的菌悬液转移100 微升至每个孔中，密封平板并在37 ℃孵育14 天后观察细菌的生长情况。mic定义为与阳性对照相比没有明显可见细菌生长的最低浓度。
25.本发明构建微生物序列参考库以及结核分枝杆菌耐药参考库，为其他分析系统的构建提供了理论基础，具有广泛的应用前景；本发明给检测菌株耐药性质提供应用基础，具有广泛的应用前景。
26.除上述优选实施例外，本发明还有其他的实施方式，本领域技术人员可以根据本发明作出各种改变和变形，只要不脱离本发明的精神，均应属于本发明权利要求书中所定义的范围。