Molecule Information

General Information of the Molecule (ID: Mol01998)

• Name: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) ,Mycobacterium tuberculosis
• Synonyms: inhA; Rv1484; MTCY277.05
• Molecule Type: Protein
• Gene Name: INHA
• Gene ID: 886523
• Sequence:
  MTGLLDGKRILVSGIITDSSIAFHIARVAQEQGAQLVLTGFDRLRLIQRITDRLPAKAPL
  LELDVQNEEHLASLAGRVTEAIGAGNKLDGVVHSIGFMPQTGMGINPFFDAPYADVSKGI
  HISAYSYASMAKALLPIMNPGGSIVGMDFDPSRAMPAYNWMTVAKSALESVNRFVAREAG
  KYGVRSNLVAAGPIRTLAMSAIVGGALGEEAGAQIQLLEEGWDQRAPIGWNMKDATPVAK
  TVCALLSDWLPATTGDIIYADGGAHTQLL
• Function: Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, which is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls. Catalyzes the NADH-dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier protein], an essential step in the fatty acid elongation cycle of the FAS-II pathway. Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates. The mycobacterial FAS-II system utilizes the products of the FAS-I system as primers to extend fatty acyl chain lengths up to C56, forming the meromycolate chain that serves as the precursor for final mycolic acids.
• Uniprot ID: INHA_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

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Isoniazid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Mycolicibacterium smegmatis infection [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Isoniazid
• Molecule Alteration: Missense mutation; p.G141E
• 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 [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Isoniazid
• Molecule Alteration: Missense mutation; p.S94A
• 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 [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Isoniazid
• Molecule Alteration: Missense mutation; p.I194T
• 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: Tuberculosis [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Isoniazid
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: Monoresistance to rifampicin and isoniazid was found in 11% (95% CI: 0.077-0.150; p, 0.087) and 8.5% (95% CI: 0.056-0.123; p, 0.692) of all the patients, respectively. Resistance to RIF and INH among newly diagnosed patients was 10.2% and 8.6%, while among previously treated patients, resistance to RIF and INH was 23.5% and 5.9% respectively. Furthermore, 4.9% of the samples from newly diagnosed with INH monoresistance, were found to have mutations in the InhA region while 8.6% had mutations in the katG region, a condition that can lead to phenotypic isoniazid drug resistance.

Prothionamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Mycolicibacterium smegmatis infection [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.G141E
• 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 [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.S94A
• 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 [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.I194T
• 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.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Tuberculosis [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: Monoresistance to rifampicin and isoniazid was found in 11% (95% CI: 0.077-0.150; p, 0.087) and 8.5% (95% CI: 0.056-0.123; p, 0.692) of all the patients, respectively. Resistance to RIF and INH among newly diagnosed patients was 10.2% and 8.6%, while among previously treated patients, resistance to RIF and INH was 23.5% and 5.9% respectively. Furthermore, 4.9% of the samples from newly diagnosed with INH monoresistance, were found to have mutations in the InhA region while 8.6% had mutations in the katG region, a condition that can lead to phenotypic isoniazid drug resistance.

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
• Ref 2: Rifampicin and isoniazid drug resistance among patients diagnosed with pulmonary tuberculosis in southwestern Uganda .PLoS One. 2021 Oct 29;16(10):e0259221. doi: 10.1371/journal.pone.0259221. eCollection 2021. 10.1371/journal.pone.0259221