Molecule Information

General Information of the Molecule (ID: Mol01997)

• Name: HTH-type transcriptional regulator EthR (ETHR) ,Mycobacterium tuberculosis
• Synonyms: ethR; etaR; Rv3855
• Molecule Type: Protein
• Gene Name: ETHR
• Gene ID: 886189
• Sequence:
  MTTSAASQASLPRGRRTARPSGDDRELAILATAENLLEDRPLADISVDDLAKGAGISRPT
  FYFYFPSKEAVLLTLLDRVVNQADMALQTLAENPADTDRENMWRTGINVFFETFGSHKAV
  TRAGQAARATSVEVAELWSTFMQKWIAYTAAVIDAERDRGAAPRTLPAHELATALNLMNE
  RTLFASFAGEQPSVPEARVLDTLVHIWVTSIYGENR
• Function: Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).
• Uniprot ID: ETHR_MYCTU

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

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Prothionamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Mycolicibacterium smegmatis infection [1]

• Resistant Disease: Mycolicibacterium smegmatis infection [ICD-11: 1B2Z.6]
• Resistant Drug: Prothionamide
• Molecule Alteration: Missense mutation; p.V152M
• 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.R216C
• 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