Drug Information

Drug (ID: DG01064) and It's Reported Resistant Information

• Name: Prothionamide
• Synonyms: Protionamide; prothionamide; 14222-60-7; 2-propylpyridine-4-carbothioamide; Ektebin; Protionamid; Trevintix; Peteha; 2-Propyl-thioisonicotinamide; 2-Propylthioisonicotinamide; Tuberex; Protionamidum; Protionizina; Tebeform; 2-Propylisonicotinylthioamide; 4-Pyridinecarbothioamide, 2-propyl-; 2-Propyl-4-pyridinecarbothioamide; TH-1321; 2-Propyl-4-thiocarbamoylpyridine; RP 9778; Isonicotinamide, 2-propylthio-; 9778 R.P.; 1321 TH; UNII-76YOO33643; Prothionamidum; RP-9778; Protionamide (Prothionamide); MLS000042521; Protionamida; 76YOO33643; NSC-758962; NCGC00095164-01; SMR000047660; DSSTox_CID_25940; DSSTox_RID_81238; DSSTox_GSID_45940; Protionamidum [INN-Latin]; Protionamida [INN-Spanish]; Trevintix (TN); CAS-14222-60-7; Protionamide (INN); TH 1321; SR-05000001518; EINECS 238-093-7; BRN 0118164; Protion; Protionamide [INN:BAN:DCF]; Prothionamide (JP17); Opera_ID_999; Spectrum2_000019; Spectrum3_001964; SCHEMBL74572; BSPBio_003564; 5-22-02-00376 (Beilstein Handbook Reference); MLS001201789; MLS006011877; SPECTRUM1505316; SPBio_000057; CHEMBL1378024; DTXSID7045940; CHEBI:32066; KBio3_002911; Prothionamide, >=99% (HPLC); 2-Propyl-4-thiocarbamoyl pyridine; HMS1922D06; HMS2090J11; HMS2235M12; HMS3372K04; HMS3655O18; HMS3715G13; KUC109576N; Pharmakon1600-01505316; ALBB-010476; BCP13522; HY-B0306; KSC-27-052D; ZINC3874803; Tox21_111463; BBL010291; BDBM50499814; CCG-40049; MFCD00464119; NSC758962; s1881; STK366469; STL454225; AKOS005172678; Tox21_111463_1; 1321-TH; AC-4518; DB12667; KS-1282; MCULE-3817450515; NSC 758962; 2-propylpyridine-4-carbimidothioic acid; NCGC00095164-02; NCGC00095164-03; NCGC00095164-04; NCGC00095164-05; M860; SBI-0207058.P001; DB-042615; Protionamide 100 microg/mL in Acetonitrile; 4-Pyridinecarbothioamide, 2-propyl- (9CI); FT-0630412; P2302; SW199462-2; D01195; D88012; AB00393463-12; AB01093435-02; AB01093435_03; AB01093435_04; A807874; Q866657; Q-201638; SR-05000001518-1; SR-05000001518-2; SR-05000001518-3; BRD-K75360161-001-09-9
• Indication:
  In total 1 Indication(s)
  Tuberculosis [ICD-11: 1B10]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Mycobacterial diseases [ICD-11: 1B2Z ]; [1]
• Target: Bacterial Fatty acid synthetase I (Bact inhA); INHA_MYCTU; [1]
• Formula: C9H12N2S
• IsoSMILES: CCCC1=NC=CC(=C1)C(=S)N
• InChI: 1S/C9H12N2S/c1-2-3-8-6-7(9(10)12)4-5-11-8/h4-6H,2-3H2,1H3,(H2,10,12)
• InChIKey: VRDIULHPQTYCLN-UHFFFAOYSA-N
• PubChem CID: 666418
• ChEBI ID: CHEBI:32066
• TTD Drug ID: D0L7UQ

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [1]

• Molecule Alteration: Missense mutation; p.G141E
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [1]

• Molecule Alteration: Missense mutation; p.S94A
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [1]

• Molecule Alteration: Missense mutation; p.I194T
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.P28S
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.L35R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.G42D
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.D56Y
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.D58G
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.W69C
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.H102P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.C137R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Y141N
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.T186P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.T189R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Q246P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.S266R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.R279E
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.S329P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.P334A
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.A341V
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.N345K
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.A352E
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.M372R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.C403Y
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.F480S
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.I161V
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.G324R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Q254P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.S266R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.S266R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.M373T
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.L267V
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.R239Q
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.S266R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Q165P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Q246R
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.L446P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.V179F
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.A395D
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.Q254P
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.G43S
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [1]

• Molecule Alteration: Missense mutation; p.W69C
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: HTH-type transcriptional regulator EthR (ETHR) [1]

• Molecule Alteration: Missense mutation; p.V152M
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strain H37Rv ATCC27294 T; 83332
• Experiment for Molecule Alteration: Sequencing analysis
• Experiment for Drug Resistance: In vitro drug susceptibility testing
• Mechanism Description: Notably, isoniazid is activated by the enzyme catalase-peroxidase, KatG, encoded by katG, whereas prothionamide is activated by the flavin monoxygenase, EthA, encoded by ethA. Mutations in katG and ethA are associated with individual isoniazid and prothionamide/ethionamide resistance, respectively. The ndh gene coding for NADH dehydrogenase, Ndh, was first identified as a new mechanism for INHR in Mycobacterium smegmatis. The mutations in ndh gene cause defects in the oxidation of NADH to NAD, which results in NADH accumulation and NAD depletion. The increased level of NADH inhibits the binding of isoniazid-NAD adduct to the active site of the InhA enzyme, which disturbs the regulation of enzyme activity and may cause co-resistance to isoniazid and prothionamide. EthR, a member of the TetR/CamR family, is a repressor of ethA. EthR regulates the transcription of ethA by coordinated octamerization on a 55-bp operator situated in the ethA-R intergenic region. Impeding EthR function leads to enhanced mycobacterial sensitivity to prothionamide, whereas mutations in ethR encoding a negative transcriptional regulator of the expression of EthA lead to prothionamide resistance. Finally, MshA, a member of the glycosyltransferase family, is a key enzyme involved in mycothiol biosynthesis in M. tuberculosis. Mutations in mshA coding MshA have been proposed to create a disturbance in prothionamide/ethionamide activation.

Key Molecule: HTH-type transcriptional regulator EthR (ETHR) [1]

• Molecule Alteration: Missense mutation; p.R216C
• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• 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: 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