Molecule Information

General Information of the Molecule (ID: Mol01996)

• Name: FAD-containing monooxygenase EthA (ETHA) ,Mycobacterium tuberculosis
• Synonyms: ethA; etaA; Rv3854c
• Molecule Type: Protein
• Gene Name: ETHA
• Gene ID: 886175
• Sequence:
  MTEHLDVVIVGAGISGVSAAWHLQDRCPTKSYAILEKRESMGGTWDLFRYPGIRSDSDMY
  TLGFRFRPWTGRQAIADGKPILEYVKSTAAMYGIDRHIRFHHKVISADWSTAENRWTVHI
  QSHGTLSALTCEFLFLCSGYYNYDEGYSPRFAGSEDFVGPIIHPQHWPEDLDYDAKNIVV
  IGSGATAVTLVPALADSGAKHVTMLQRSPTYIVSQPDRDGIAEKLNRWLPETMAYTAVRW
  KNVLRQAAVYSACQKWPRRMRKMFLSLIQRQLPEGYDVRKHFGPHYNPWDQRLCLVPNGD
  LFRAIRHGKVEVVTDTIERFTATGIRLNSGRELPADIIITATGLNLQLFGGATATIDGQQ
  VDITTTMAYKGMMLSGIPNMAYTVGYTNASWTLKADLVSEFVCRLLNYMDDNGFDTVVVE
  RPGSDVEERPFMEFTPGYVLRSLDELPKQGSRTPWRLNQNYLRDIRLIRRGKIDDEGLRF
  AKRPAPVGV
• Function: Monooxygenase able to convert a wide range of ketones to the corresponding esters or lactones via a Baeyer-Villiger oxidation reaction. Can act on long-chain aliphatic ketones (2-hexanone to 2-dodecanone) and on aromatic ketones (phenylacetone and benzylacetone). Is also able to catalyze enantioselective sulfoxidation of methyl-p-tolylsulfide. In vivo, likely functions as a BVMO, but the exact nature of the physiological substrate(s) remains to be established.
• Uniprot ID: ETHA_MYCTU

Kingdom: N.A.
Phylum: Actinobacteria
Class: Actinomycetia
Order: 85007
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: Mycobacterium tuberculosis

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Perchlozone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Multidrug-resistant tuberculosis [1]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Resistant Drug: Perchlozone
• Molecule Alteration: Frameshift mutation; c.106 GA>G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain; 1313
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: Perchlozone is a prodrug that is activated by EthA and inhibits the HadABC complex.A resistance to perchlozone was shown by in vitro experiments and was mediated by both ethA and hadA mutations.

Disease Class: Multidrug-resistant tuberculosis [1]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Resistant Drug: Perchlozone
• Molecule Alteration: Frameshift mutation; c.314ACC > ATC (p.Thr > Ile)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain; 1313
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: Perchlozone is a prodrug that is activated by EthA and inhibits the HadABC complex.A resistance to perchlozone was shown by in vitro experiments and was mediated by both ethA and hadA mutations.

Disease Class: Multidrug-resistant tuberculosis [1]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Resistant Drug: Perchlozone
• Molecule Alteration: Frameshift mutation; c.702 CT > C
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain; 1313
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: Perchlozone is a prodrug that is activated by EthA and inhibits the HadABC complex.A resistance to perchlozone was shown by in vitro experiments and was mediated by both ethA and hadA mutations.

Disease Class: Multidrug-resistant tuberculosis [1]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Resistant Drug: Perchlozone
• Molecule Alteration: Frameshift mutation; c.106 GA > G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain; 1313
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: Perchlozone is a prodrug that is activated by EthA and inhibits the HadABC complex.A resistance to perchlozone was shown by in vitro experiments and was mediated by both ethA and hadA mutations.

Prothionamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Mycolicibacterium smegmatis infection [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.P28S
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.L35R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.G42D
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.D56Y
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.D58G
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.W69C
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.H102P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.C137R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Y141N
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.T186P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.T189R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Q246P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S266R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.R279E
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S329P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.P334A
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.A341V
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.N345K
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.A352E
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.M372R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.C403Y
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.F480S
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.I161V
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.G324R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Q254P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S266R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S266R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.M373T
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.L267V
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.R239Q
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S266R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Q165P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Q246R
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.L446P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.V179F
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.A395D
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.Q254P
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.G43S
• 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 [2]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.W69C
• 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.

References

• Ref 1: Genetic Variation Putatively Associated with Mycobacterium tuberculosis Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis .Antibiotics (Basel). 2020 Oct 3;9(10):669. doi: 10.3390/antibiotics9100669. 10.3390/antibiotics9100669
• Ref 2: 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