General Information of the Molecule (ID: Mol00856)
Name
Catalase-peroxidase (KATG) ,Mycobacterium tuberculosis
Synonyms
CP; Peroxidase/catalase; Rv1908c; MTCY180.10
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Molecule Type
Protein
Gene Name
katG
Gene ID
885638
Sequence
MPEQHPPITETTTGAASNGCPVVGHMKYPVEGGGNQDWWPNRLNLKVLHQNPAVADPMGA
AFDYAAEVATIDVDALTRDIEEVMTTSQPWWPADYGHYGPLFIRMAWHAAGTYRIHDGRG
GAGGGMQRFAPLNSWPDNASLDKARRLLWPVKKKYGKKLSWADLIVFAGNCALESMGFKT
FGFGFGRVDQWEPDEVYWGKEATWLGDERYSGKRDLENPLAAVQMGLIYVNPEGPNGNPD
PMAAAVDIRETFRRMAMNDVETAALIVGGHTFGKTHGAGPADLVGPEPEAAPLEQMGLGW
KSSYGTGTGKDAITSGIEVVWTNTPTKWDNSFLEILYGYEWELTKSPAGAWQYTAKDGAG
AGTIPDPFGGPGRSPTMLATDLSLRVDPIYERITRRWLEHPEELADEFAKAWYKLIHRDM
GPVARYLGPLVPKQTLLWQDPVPAVSHDLVGEAEIASLKSQIRASGLTVSQLVSTAWAAA
SSFRGSDKRGGANGGRIRLQPQVGWEVNDPDGDLRKVIRTLEEIQESFNSAAPGNIKVSF
ADLVVLGGCAAIEKAAKAAGHNITVPFTPGRTDASQEQTDVESFAVLEPKADGFRNYLGK
GNPLPAEYMLLDKANLLTLSAPEMTVLVGGLRVLGANYKRLPLGVFTEASESLTNDFFVN
LLDMGITWEPSPADDGTYQGKDGSGKVKWTGSRVDLVFGSNSELRALVEVYGADDAQPKF
VQDFVAAWDKVMNLDRFDVR
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Function
Bifunctional enzyme with both catalase and broad-spectrum peroxidase activity, oxidizing various electron donors including NADP(H). Protects M.tuberculosis against toxic reactive oxygen species (ROS) including hydrogen peroxide as well as organic peroxides and thus contributes to its survival within host macrophages by countering the phagocyte oxidative burst. Also displays efficient peroxynitritase activity, which may help the bacterium to persist in macrophages.
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Uniprot ID
KATG_MYCTU
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Kingdom: N.A.
Phylum: Actinobacteria
Class: Actinomycetia
Order: Corynebacteriales
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: Mycobacterium tuberculosis
Type(s) of Resistant Mechanism of This Molecule
  DISM: Drug Inactivation by Structure Modification
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
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Isoniazid
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Disease Class: HIV-infected patients with tuberculosis [1]
Resistant Disease HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
Resistant Drug Isoniazid
Molecule Alteration Expression
Down-regulation
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.
Disease Class: Pneumoconiosis complicated with tuberculosis [2]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Pneumoconiosis complicated with tuberculosis [2]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315N
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.
Disease Class: Pneumoconiosis complicated with tuberculosis [2]
Resistant Disease Pneumoconiosis complicated with tuberculosis [ICD-11: CA60.Y]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.A431V
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315N
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.A312P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.A264V
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.N660D
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.L147P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.C20R
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.T308P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.T275A
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.D142G
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S211G
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.M126I
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.W91R
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315G
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G490S
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.V581G
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.A110V
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G466R
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G279V
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.L436P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.N508D
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.P92S
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G125S
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.Q127P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.V431A
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G490S
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.Q461P
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.E607A
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.H417Q
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G111S
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.G33V
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.
Disease Class: Mycolicibacterium smegmatis infection [3]
Resistant Disease Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.W191R
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.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Urinary tuberculosis [4]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S531L
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.
Disease Class: Urinary tuberculosis [4]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
Resistant Drug Isoniazid
Molecule Alteration Missense mutation
p.S315T1
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.
Rifampin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Urinary tuberculosis [4]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
Resistant Drug Rifampin
Molecule Alteration Missense mutation
p.S531L
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.
Disease Class: Urinary tuberculosis [4]
Resistant Disease Urinary tuberculosis [ICD-11: 1G80.0]
Resistant Drug Rifampin
Molecule Alteration Missense mutation
p.S315T1
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.
References
Ref 1 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 2 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 3 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 4 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

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