Drug Information

Drug (ID: DG00136) and It's Reported Resistant Information
Name
Isoniazid
Synonyms
Abdizide; Andrazide; Anidrasona; Antimicina; Antituberkulosum; Armacide; Armazid; Armazide; Atcotibine; Azuren; Bacillen; Bacillin; Cedin; Cemidon; Chemiazid; Chemidon; Continazine; Cortinazine; Cotinazin; Cotinizin; Defonin; Dibutin; Diforin; Dinacrin; Ditubin; Ebidene; Eralon; Ertuban; Eutizon; Evalon; Fetefu; Fimalene; HIA; Hidranizil; Hidrasonil; Hidrulta; Hidrun; Hycozid; Hydra; Hydrazid; Hydrazide; Hyozid; Hyzyd; INH; Idrazil; Inah; Inizid; Iscotin; Isidrina; Ismazide; Isobicina; Isocid; Isocidene; Isocotin; Isohydrazide; Isokin; Isolyn; Isonerit; Isonex; Isoniacid; Isoniazida; Isoniazide; Isoniazidum; Isonicazide; Isonicid; Isonico; Isonicotan; Isonicotil; Isonicotinhydrazid; Isonicotinohydrazide; Isonide; Isonidrin; Isonikazid; Isonilex; Isonin; Isonindon; Isonirit; Isoniton; Isonizida; Isonizide; Isotamine; Isotebe; Isotebezid; Isotinyl; Isozid; Isozide; Isozyd; LANIZID; Laniazid; Laniozid; Mybasan; Neoteben; Neoxin; Neumandin; Nevin; Niadrin; Nicazide; Nicetal; Nicizina; Niconyl; Nicotibina; Nicotibine; Nicotisan; Nicozide; Nidaton; Nidrazid; Nikozid; Niplen; Nitadon; Niteban; Nydrazid; Nyscozid; Pelazid; Percin; Phthisen; Pycazide; Pyreazid; Pyricidin; Pyridicin; Pyrizidin; Raumanon; Razide; Retozide; Rimicid; Rimifon; Rimiphone; Rimitsid; Robiselin; Robisellin; Roxifen; Sanohidrazina; Sauterazid; Sauterzid; Stanozide; Tebecid; Tebemid; Tebenic; Tebexin; Tebilon; Tebos; Teebaconin; Tekazin; Tibazide; Tibemid; Tibiazide; Tibinide; Tibison; Tibivis; Tibizide; Tibusan; Tisin; Tisiodrazida; Tizide; Tubazid; Tubazide; Tubeco; Tubecotubercid; Tubercid; Tuberian; Tubicon; Tubilysin; Tubizid; Tubomel; Tyvid; Unicocyde; Unicozyde; Vazadrine; Vederon; Zidafimia; Zinadon; Zonazide; Hid rasonil; Isoco tin; Isoniazid SA; Isozid e; Nidra zid; Rimif on; BP 5015; Bp 5 015; FSR 3; I0138; INHd20; L 1945; Nitebannsc 9659; Preparation 6424; RP 5015; AZT + Isoniazid; Cedin (Aerosol); Dow-Isoniazid; FRS-3; FSR-3; Ido-tebin; In-73; Inh-Burgthal; Isoniazid & EEP; Isoniazid & Propolis; Laniazid (TN); Neo-Tizide; Nydrazid (TN); RP-5015; TB-Phlogin; TB-Razide; TB-Vis; Usaf cb-2; I.A.I; RU-EF-Tb; RY-EF-Tb; I.A.I.
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Indication
In total 1 Indication(s)
HIV-infected patients with tuberculosis [ICD-11: 1B10-1B14]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (3 diseases)
Bifidobacterium [ICD-11: XN33F]
[2]
Mycobacterial diseases [ICD-11: 1B2Z ]
[3]
Tuberculosis [ICD-11: 1B10]
[6]
Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
Pneumoconiosis [ICD-11: CA60]
[4]
Tuberculosis [ICD-11: 1B10]
[5]
Tuberculous sclerokeratitis [ICD-11: 1B12]
[7]
Urinary tuberculosis [ICD-11: 1G80]
[8]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
HIV associated with tuberculosis [ICD-11: 1C60]
[9]
Mycobacterial diseases [ICD-11: 1B2Z ]
[1]
Target Bacterial Fatty acid synthetase I (Bact inhA) INHA_MYCTU [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C6H7N3O
IsoSMILES
C1=CN=CC=C1C(=O)NN
InChI
1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)
InChIKey
QRXWMOHMRWLFEY-UHFFFAOYSA-N
PubChem CID
3767
ChEBI ID
CHEBI:6030
TTD Drug ID
D09XQF
VARIDT ID
DR00422
INTEDE ID
DR0886
DrugBank ID
DB00951
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-01: Infectious/parasitic diseases
Click to Show/Hide the Resistance Disease of This Class
Tuberculosis [ICD-11: 1B10]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [5]
Resistant Disease Tuberculosis [ICD-11: 1B10.0]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis H37Rv 83332
Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description Monoresistance to rifampicin and isoniazid was found in 11% (95% CI: 0.077-0.150; p, 0.087) and 8.5% (95% CI: 0.056-0.123; p, 0.692) of all the patients, respectively. Resistance to RIF and INH among newly diagnosed patients was 10.2% and 8.6%, while among previously treated patients, resistance to RIF and INH was 23.5% and 5.9% respectively. Furthermore, 4.9% of the samples from newly diagnosed with INH monoresistance, were found to have mutations in the InhA region while 8.6% had mutations in the katG region, a condition that can lead to phenotypic isoniazid drug resistance.
Key Molecule: Outer membrane protein A (OmpA) [6]
Resistant Disease Tuberculosis [ICD-11: 1B10.0]
 Disease Info 
Molecule Alteration Expressiom
D96D
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Mycobacterium tuberculosis 1773
Experiment for
Drug Resistance		 MIC assay
Mechanism Description These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [5]
Resistant Disease Tuberculosis [ICD-11: 1B10.0]
 Disease Info 
Molecule Alteration Mutation
.
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis H37Rv 83332
Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description Monoresistance to rifampicin and isoniazid was found in 11% (95% CI: 0.077-0.150; p, 0.087) and 8.5% (95% CI: 0.056-0.123; p, 0.692) of all the patients, respectively. Resistance to RIF and INH among newly diagnosed patients was 10.2% and 8.6%, while among previously treated patients, resistance to RIF and INH was 23.5% and 5.9% respectively. Furthermore, 4.9% of the samples from newly diagnosed with INH monoresistance, were found to have mutations in the InhA region while 8.6% had mutations in the katG region, a condition that can lead to phenotypic isoniazid drug resistance.
Mycobacterial diseases [ICD-11: 1B2Z ]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S94A
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 4TRO
Mutant Type Structure Method: X-ray diffraction Resolution: 1.90  Å
PDB: 4DTI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.13
TM score: 0.99951
Amino acid change:
S94A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G141E
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.I194T
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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180
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270
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G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315N
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.A312P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.A264V
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.N660D
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.L147P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.C20R
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.T308P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.T275A
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.D142G
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S211G
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.M126I
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.W91R
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.S315G
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G490S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.V581G
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.A110V
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G466R
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G279V
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.L436P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.N508D
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.P92S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G125S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.Q127P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.V431A
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G490S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.Q461P
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.E607A
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.H417Q
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G111S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.G33V
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: Catalase-peroxidase (KATG) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Missense mutation
p.W191R
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
  Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: P-type ATPase zinc transporter Rv3270 [3]
Resistant Disease Bone infection [ICD-11: 1B2Z.9]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model E. coli XL1-Blue 562
E. coli CS109 562
M. smegmatis MC2 161 1772
Experiment for
Molecule Alteration		 Gene expression analysis
Experiment for
Drug Resistance		 Antimicrobial susceptibility assay; Intracellular drug accumulation activity assay
Mechanism Description Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: NAD-dependent protein deacylase Sir2 (SIR2) [1]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli 668369
Mycobacterium smegmatis mc2155 246196
Experiment for
Molecule Alteration		 Quantitative Real-Time PCR
Experiment for
Drug Resistance		 Colony forming units determination assay
Mechanism Description MSMEG_5175 regulates diverse cellular processes resulting in an increase in INH resistance in mycobacteria. Overexpression of MSMEG_5175 results in up-regulation of 34 proteins and down-regulation of 72 proteins, which involve in diverse cellular processes including metabolic activation, transcription and translation, antioxidant, and DNA repair. Down-regulation of catalase peroxidase (katG) expression in both mRNA and protein levels were observed in mc(2)155-MS5175 strain, suggesting that a decrease in cellular NAD content and down-regulation of katG expression contribute to the higher resistance to INH in mc(2)155-MS5175.
Key Molecule: D-inositol 3-phosphate glycosyltransferase (MSHA) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Non-synonymous mutation
p.F355S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
Key Molecule: D-inositol 3-phosphate glycosyltransferase (MSHA) [10]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
 Disease Info 
Molecule Alteration Non-synonymous mutation
p.N111S
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strain H37Rv ATCC27294 T 83332
Experiment for
Molecule Alteration		 Sequencing analysis
Experiment for
Drug Resistance		 In vitro drug susceptibility testing
Mechanism Description Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.
HIV associated with tuberculosis [ICD-11: 1C60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Catalase-peroxidase (KATG) [11]
Resistant Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Cell growth Inhibition hsa05200
In Vitro Model Mycobacterium smegmatis mc2155 246196
Mycobacterium smegmatis mc2155-Cu 246196
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 MIC assay
Mechanism Description As a prodrug, INH needs to be activated by katG to execute its antibiotic function. katG is a bifunctional enzyme with both catalase and peroxidase activity and catalyzes the coupling of INH with NAD+ to form the isonicotinic acyl-NAD complex, which binds to the enoyl-acyl carrier protein reductase to inhibit the synthesis of mycolic acid required for the mycobacterial cell wall. In the present study, quantitative proteomic analysis showed that the expression level of katG was down-regulated in mc2155-Cu as compared to mc2155. Down-regulation of katG expression as well as a decrease in cellular NAD level results in the higher resistance to INH in mc2155-Cu.
Key Molecule: Arylamine N-acetyltransferase 1 (NAT1) [12]
Resistant Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
Cell Pathway Regulation Cell growth Activation hsa05200
In Vitro Model Mycobacterium tuberculosis H37Rv 83332
Experiment for
Molecule Alteration		 SDS-PAGE assay
Experiment for
Drug Resistance		 Titertek multiskan assay
Mechanism Description Arylamine N-acetyltransferase (NAT), a drug-metabolizing enzyme of MTB, can acetylate INH, transferring an acetyl group from acetyl coenzyme A to the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The overexpression of NAT in Mycobacterium smegmatis showed increased resistance to INH; in addition, when the gene was knocked-out, the bacteria exhibited increased sensitivity to INH.
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Isocitrate lyase 1 (ICL1) [9]
Resistant Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strains 1773
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MIC assay
Mechanism Description Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.
Key Molecule: Isocitrate lyase 2 (ICL2) [9]
Resistant Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strains 1773
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MIC assay
Mechanism Description Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Isocitrate lyase 1 (ICL1) [9]
Sensitive Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strains 1773
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MIC assay
Mechanism Description Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.
Key Molecule: Isocitrate lyase 2 (ICL2) [9]
Sensitive Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Mycobacterium tuberculosis strains 1773
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MIC assay
Mechanism Description Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.
Urinary tuberculosis [ICD-11: 1G80]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Catalase-peroxidase (KATG) [8]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S531L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 Gene sequencing assay
Mechanism Description Regarding drug-resistance mutation profiles, the most prevalent mutation sites were katG S315T1 and rpoB S531L.
Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [8]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S531L
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 Gene sequencing assay
Mechanism Description Regarding drug-resistance mutation profiles, the most prevalent mutation sites were katG S315T1 and rpoB S531L.
Key Molecule: Catalase-peroxidase (KATG) [8]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T1
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 Gene sequencing assay
Mechanism Description Regarding drug-resistance mutation profiles, the most prevalent mutation sites were katG S315T1 and rpoB S531L.
Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [8]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T1
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Experiment for
Molecule Alteration		 Gene sequencing assay
Mechanism Description Regarding drug-resistance mutation profiles, the most prevalent mutation sites were katG S315T1 and rpoB S531L.
ICD-12: Respiratory system diseases
Click to Show/Hide the Resistance Disease of This Class
Pneumoconiosis [ICD-11: CA60]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Catalase-peroxidase (KATG) [4]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.S315T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2CCA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 2CCD
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.24
TM score: 0.99934
Amino acid change:
S315T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
P
P
E
E
Q
Q
H
H
P
P
P
P
I
I
T
T
10
|
E
E
T
T
T
T
T
T
G
G
A
A
A
A
S
S
N
N
G
G
20
|
C
C
P
P
V
V
V
V
G
G
H
H
M
M
K
K
Y
Y
P
P
30
|
V
V
E
E
G
G
G
G
G
G
N
N
Q
Q
D
D
W
W
W
W
40
|
P
P
N
N
R
R
L
L
N
N
L
L
K
K
V
V
L
L
H
H
50
|
Q
Q
N
N
P
P
A
A
V
V
A
A
D
D
P
P
M
M
G
G
60
|
A
A
A
A
F
F
D
D
Y
Y
A
A
A
A
E
E
V
V
A
A
70
|
T
T
I
I
D
D
V
V
D
D
A
A
L
L
T
T
R
R
D
D
80
|
I
I
E
E
E
E
V
V
M
M
T
T
T
T
S
S
Q
Q
P
P
90
|
W
W
W
W
P
P
A
A
D
D
Y
Y
G
G
H
H
Y
Y
G
G
100
|
P
P
L
L
F
F
I
I
R
R
M
M
A
A
W
W
H
H
A
A
110
|
A
A
G
G
T
T
Y
Y
R
R
I
I
H
H
D
D
G
G
R
R
120
|
G
G
G
G
A
A
G
G
G
G
G
G
M
M
Q
Q
R
R
F
F
130
|
A
A
P
P
L
L
N
N
S
S
W
W
P
P
D
D
N
N
A
A
140
|
S
S
L
L
D
D
K
K
A
A
R
R
R
R
L
L
L
L
W
W
150
|
P
P
V
V
K
K
K
K
K
K
Y
Y
G
G
K
K
K
K
L
L
160
|
S
S
W
W
A
A
D
D
L
L
I
I
V
V
F
F
A
A
G
G
170
|
N
N
C
C
A
A
L
L
E
E
S
S
M
M
G
G
F
F
K
K
180
|
T
T
F
F
G
G
F
F
G
G
F
F
G
G
R
R
V
V
D
D
190
|
Q
Q
W
W
E
E
P
P
D
D
E
E
V
V
Y
Y
W
W
G
G
200
|
K
K
E
E
A
A
T
T
W
W
L
L
G
G
D
D
E
E
R
R
210
|
Y
Y
S
S
G
G
K
K
R
R
D
D
L
L
E
E
N
N
P
P
220
|
L
L
A
A
A
A
V
V
Q
Q
M
M
G
G
L
L
I
I
Y
Y
230
|
V
V
N
N
P
P
E
E
G
G
P
P
N
N
G
G
N
N
P
P
240
|
D
D
P
P
M
M
A
A
A
A
A
A
V
V
D
D
I
I
R
R
250
|
E
E
T
T
F
F
R
R
R
R
M
M
A
A
M
M
N
N
D
D
260
|
V
V
E
E
T
T
A
A
A
A
L
L
I
I
V
V
G
G
G
G
270
|
H
H
T
T
F
F
G
G
K
K
T
T
H
H
G
G
A
A
G
G
280
|
P
P
A
A
D
D
L
L
V
V
G
G
P
P
E
E
P
P
E
E
290
|
A
A
A
A
P
P
L
L
E
E
Q
Q
M
M
G
G
L
L
G
G
300
|
W
W
K
K
S
S
S
S
Y
Y
G
G
T
T
G
G
T
T
G
G
310
|
K
K
D
D
A
A
I
I
T
T
S
T
G
G
I
I
E
E
V
V
320
|
V
V
W
W
T
T
N
N
T
T
P
P
T
T
K
K
W
W
D
D
330
|
N
N
S
S
F
F
L
L
E
E
I
I
L
L
Y
Y
G
G
Y
Y
340
|
E
E
W
W
E
E
L
L
T
T
K
K
S
S
P
P
A
A
G
G
350
|
A
A
W
W
Q
Q
Y
Y
T
T
A
A
K
K
D
D
G
G
A
A
360
|
G
G
A
A
G
G
T
T
I
I
P
P
D
D
P
P
F
F
G
G
370
|
G
G
P
P
G
G
R
R
S
S
P
P
T
T
M
M
L
L
A
A
380
|
T
T
D
D
L
L
S
S
L
L
R
R
V
V
D
D
P
P
I
I
390
|
Y
Y
E
E
R
R
I
I
T
T
R
R
R
R
W
W
L
L
E
E
400
|
H
H
P
P
E
E
E
E
L
L
A
A
D
D
E
E
F
F
A
A
410
|
K
K
A
A
W
W
Y
Y
K
K
L
L
I
I
H
H
R
R
D
D
420
|
M
M
G
G
P
P
V
V
A
A
R
R
Y
Y
L
L
G
G
P
P
430
|
L
L
V
V
P
P
K
K
Q
Q
T
T
L
L
L
L
W
W
Q
Q
440
|
D
D
P
P
V
V
P
P
A
A
V
V
S
S
H
H
D
D
L
L
450
|
V
V
G
G
E
E
A
A
E
E
I
I
A
A
S
S
L
L
K
K
460
|
S
S
Q
Q
I
I
R
R
A
A
S
S
G
G
L
L
T
T
V
V
470
|
S
S
Q
Q
L
L
V
V
S
S
T
T
A
A
W
W
A
A
A
A
480
|
A
A
S
S
S
S
F
F
R
R
G
G
S
S
D
D
K
K
R
R
490
|
G
G
G
G
A
A
N
N
G
G
G
G
R
R
I
I
R
R
L
L
500
|
Q
Q
P
P
Q
Q
V
V
G
G
W
W
E
E
V
V
N
N
D
D
510
|
P
P
D
D
G
G
D
D
L
L
R
R
K
K
V
V
I
I
R
R
520
|
T
T
L
L
E
E
E
E
I
I
Q
Q
E
E
S
S
F
F
N
N
530
|
S
S
A
A
A
A
P
P
G
G
N
N
I
I
K
K
V
V
S
S
540
|
F
F
A
A
D
D
L
L
V
V
V
V
L
L
G
G
G
G
C
C
550
|
A
A
A
A
I
I
E
E
K
K
A
A
A
A
K
K
A
A
A
A
560
|
G
G
H
H
N
N
I
I
T
T
V
V
P
P
F
F
T
T
P
P
570
|
G
G
R
R
T
T
D
D
A
A
S
S
Q
Q
E
E
Q
Q
T
T
580
|
D
D
V
V
E
E
S
S
F
F
A
A
V
V
L
L
E
E
P
P
590
|
K
K
A
A
D
D
G
G
F
F
R
R
N
N
Y
Y
L
L
G
G
600
|
K
K
G
G
N
N
P
P
L
L
P
P
A
A
E
E
Y
Y
M
M
610
|
L
L
L
L
D
D
K
K
A
A
N
N
L
L
L
L
T
T
L
L
620
|
S
S
A
A
P
P
E
E
M
M
T
T
V
V
L
L
V
V
G
G
630
|
G
G
L
L
R
R
V
V
L
L
G
G
A
A
N
N
Y
Y
K
K
640
|
R
R
L
L
P
P
L
L
G
G
V
V
F
F
T
T
E
E
A
A
650
|
S
S
E
E
S
S
L
L
T
T
N
N
D
D
F
F
F
F
V
V
660
|
N
N
L
L
L
L
D
D
M
M
G
G
I
I
T
T
W
W
E
E
670
|
P
P
S
S
P
P
A
A
D
D
D
D
G
G
T
T
Y
Y
Q
Q
680
|
G
G
K
K
D
D
G
G
S
S
G
G
K
K
V
V
K
K
W
W
690
|
T
T
G
G
S
S
R
R
V
V
D
D
L
L
V
V
F
F
G
G
700
|
S
S
N
N
S
S
E
E
L
L
R
R
A
A
L
L
V
V
E
E
710
|
V
V
Y
Y
G
G
A
A
D
D
D
D
A
A
Q
Q
P
P
K
K
720
|
F
F
V
V
Q
Q
D
D
F
F
V
V
A
A
A
A
W
W
D
D
730
|
K
K
V
V
M
M
N
N
L
L
D
D
R
R
F
F
D
D
V
V
740
|
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Mycobacterium tuberculosis H37Rv1 1773
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description Isoniazid is a hydrazine chemical synthetic drug, which is able to be oxidized to isonicotinic acid by the catalase-peroxidase encoded by the katG gene that participates in the synthesis of coenzyme I (NAD) to inhibit the biosynthesis of mycolic acid of the cell wall in Mycobacterium tuberculosis, so as to damage the MDR-TB's barricade of resisting antioxygen and invasion. Due to deletion or mutation in the katG gene, resistance is able to be generated as the enzymatic activity is lost or degraded, thus, inhibiting the activation of Isoniazid.
Key Molecule: Catalase-peroxidase (KATG) [4]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.S315N
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Mycobacterium tuberculosis H37Rv1 1773
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description Isoniazid is a hydrazine chemical synthetic drug, which is able to be oxidized to isonicotinic acid by the catalase-peroxidase encoded by the katG gene that participates in the synthesis of coenzyme I (NAD) to inhibit the biosynthesis of mycolic acid of the cell wall in Mycobacterium tuberculosis, so as to damage the MDR-TB's barricade of resisting antioxygen and invasion. Due to deletion or mutation in the katG gene, resistance is able to be generated as the enzymatic activity is lost or degraded, thus, inhibiting the activation of Isoniazid.
Key Molecule: Catalase-peroxidase (KATG) [4]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.A431V
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Mycobacterium tuberculosis isolates 1773
Mycobacterium tuberculosis H37Rv1 1773
Experiment for
Molecule Alteration		 qRT-PCR
Mechanism Description Isoniazid is a hydrazine chemical synthetic drug, which is able to be oxidized to isonicotinic acid by the catalase-peroxidase encoded by the katG gene that participates in the synthesis of coenzyme I (NAD) to inhibit the biosynthesis of mycolic acid of the cell wall in Mycobacterium tuberculosis, so as to damage the MDR-TB's barricade of resisting antioxygen and invasion. Due to deletion or mutation in the katG gene, resistance is able to be generated as the enzymatic activity is lost or degraded, thus, inhibiting the activation of Isoniazid.
ICD-X: Extension Codes
Click to Show/Hide the Resistance Disease of This Class
Bifidobacterium [ICD-11: XN33F]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Catalase (CAT) [2]
Resistant Disease bifidobacterium adolescentis infection [ICD-11: XN33F]
 Disease Info 
Molecule Alteration Function
RV0005; p.Ala403Ser
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Bifidobacterial strains 1763
Experiment for
Molecule Alteration		 PCR; Catalase foam assay; Catalase gel assay
Experiment for
Drug Resistance		 Growth curve assay; Spot assay; Anti-tubercular drug uptake and surface assay; Adaptability assay; FE-SEM assay; MIC assay; Particle size assay
Mechanism Description The current study aims to understand the resistance of Bifidobacterium adolescentis to different anti-tubercular drugs (first-line oral tuberculosis drugs). The bacteria were grown with anti-tubercular drugs such as isoniazid, pyrazinamide, and streptomycin to better understand the resistance phenomena. It was found that even at tenfold higher concentrations, growth rates remained unchanged. In addition, a small number of bacteria were found to aggregate strongly, a property that protects against the toxicity of the drug. Further FE-SEM (Field Emission Scanning Electron Microscopy) analysis revealed that some bacteria became excessively long, elongated, and protruded on the surface. Size scattering analysis confirmed the presence of bifidobacteria in the size range of 1.0-100 um. After whole genome sequence analysis, certain mutations were found in the relevant gene. In vitro, foam formation and growth in the presence of H2O2 and HPLC (High Performance Liquid Chromatography) studies provide additional evidence for the presence of catalase. According to RAST (Rapid Annotation Using Subsystems Technology) annotation and CARD (Comprehensive Antibiotic Resistance Database analysis), there were not many components in the genome that were resistant to antibiotics. Whole genome sequence (WGS) analysis does not show the presence of bacteriocins and antibiotic resistance genes, but few hypothetical proteins were observed. 3D structure and docking studies suggest their interaction with specific ligands.
References
Ref 1 Functional Characterization of Sirtuin-like Protein in Mycobacterium smegmatis. J Proteome Res. 2015 Nov 6;14(11):4441-9. doi: 10.1021/acs.jproteome.5b00359. Epub 2015 Sep 29.
Ref 2 Bifidobacterium adolescentis is resistant to pyrazinamide, isoniazid, and streptomycin. Sci Rep. 2024 Nov 28;14(1):29562.
Ref 3 P-type ATPase zinc transporter Rv3270 of Mycobacterium tuberculosis enhances multi-drug efflux activity. Microbiology (Reading). 2024 Feb;170(2):001441.
Ref 4 Analysis of mutational characteristics of the drug-resistant gene katG in multi-drug resistant Mycobacterium tuberculosis L-form among patients with pneumoconiosis complicated with tuberculosis .Mol Med Rep. 2014 May;9(5):2031-5. doi: 10.3892/mmr.2014.2045. Epub 2014 Mar 13. 10.3892/mmr.2014.2045
Ref 5 Rifampicin and isoniazid drug resistance among patients diagnosed with pulmonary tuberculosis in southwestern Uganda .PLoS One. 2021 Oct 29;16(10):e0259221. doi: 10.1371/journal.pone.0259221. eCollection 2021. 10.1371/journal.pone.0259221
Ref 6 Overexpression of outer membrane protein A (OmpA) increases aminoglycoside sensitivity in mycobacteria. BMC Microbiol. 2024 Nov 13;24(1):472.
Ref 7 Tuberculous Scleritis and Multidrug ResistanceOcul Immunol Inflamm. 2021 Jan 8:1-10. doi: 10.1080/09273948.2020.1853176. Online ahead of print.
Ref 8 Clinical Features and Drug-Resistance Profile of Urinary Tuberculosis in South-Western China: A Cross-sectional Study .Medicine (Baltimore). 2016 May;95(19):e3537. doi: 10.1097/MD.0000000000003537. 10.1097/MD.0000000000003537
Ref 9 Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nat Commun. 2014 Jun 30;5:4306. doi: 10.1038/ncomms5306.
Ref 10 Detection of novel mutations associated with independent resistance and cross-resistance to isoniazid and prothionamide in Mycobacterium tuberculosis clinical isolates .Clin Microbiol Infect. 2019 Aug;25(8):1041.e1-1041.e7. doi: 10.1016/j.cmi.2018.12.008. Epub 2018 Dec 22. 10.1016/j.cmi.2018.12.008
Ref 11 Proteomic Analysis of Drug-Resistant Mycobacteria: Co-Evolution of Copper and INH Resistance. PLoS One. 2015 Jun 2;10(6):e0127788. doi: 10.1371/journal.pone.0127788. eCollection 2015.
Ref 12 Cloning and characterization of arylamine N-acetyltransferase genes from Mycobacterium smegmatis and Mycobacterium tuberculosis: increased expression results in isoniazid resistance. J Bacteriol. 1999 Feb;181(4):1343-7. doi: 10.1128/JB.181.4.1343-1347.1999.

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