Disease Information

General Information of the Disease (ID: DIS00152)

• Name: Tuberculosis
• ICD: ICD-11: 1B10

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cycloserine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Alanine racemase (ALR) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cycloserine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Experiment for Drug Resistance: Drug susceptibility testing
• Mechanism Description: Since D-cycloserine is a structural analogue of D-alanine, enzymes with substrates of D-alanine are the drug targets of D-cycloserine in mycobacteria. These enzymes include D-alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl), which are required for the synthesis of peptidoglycan in the mycobacterial cell wall. Overexpression of alr and ddl has been shown to cause resistance to D-cycloserine in Mycobacterium smegmatis. Moreover, SNPs in these genes were also found in resistant Mycobacterium tuberculosis. Consistent with the cell-wall peptidoglycan being a target of D-cycloserine, previous studies have shown that D-cycloserine competitively inhibits both Alr and Ddl. However, a more recent metabolomic study showed that Ddl is a primary target of D-cycloserine and is preferentially inhibited over Alr in M. tuberculosis.

Key Molecule: D-alanine--D-alanine ligase (DDL) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cycloserine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Experiment for Drug Resistance: Drug susceptibility testing
• Mechanism Description: Since D-cycloserine is a structural analogue of D-alanine, enzymes with substrates of D-alanine are the drug targets of D-cycloserine in mycobacteria. These enzymes include D-alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl), which are required for the synthesis of peptidoglycan in the mycobacterial cell wall. Overexpression of alr and ddl has been shown to cause resistance to D-cycloserine in Mycobacterium smegmatis. Moreover, SNPs in these genes were also found in resistant Mycobacterium tuberculosis. Consistent with the cell-wall peptidoglycan being a target of D-cycloserine, previous studies have shown that D-cycloserine competitively inhibits both Alr and Ddl. However, a more recent metabolomic study showed that Ddl is a primary target of D-cycloserine and is preferentially inhibited over Alr in M. tuberculosis.

Key Molecule: Alanine racemase (ALR) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Missense mutation; p.C1030T
• Resistant Drug: Cycloserine
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Experiment for Drug Resistance: Drug susceptibility testing
• Mechanism Description: Since D-cycloserine is a structural analogue of D-alanine, enzymes with substrates of D-alanine are the drug targets of D-cycloserine in mycobacteria. These enzymes include D-alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl), which are required for the synthesis of peptidoglycan in the mycobacterial cell wall. Overexpression of alr and ddl has been shown to cause resistance to D-cycloserine in Mycobacterium smegmatis. Moreover, SNPs in these genes were also found in resistant Mycobacterium tuberculosis. Consistent with the cell-wall peptidoglycan being a target of D-cycloserine, previous studies have shown that D-cycloserine competitively inhibits both Alr and Ddl. However, a more recent metabolomic study showed that Ddl is a primary target of D-cycloserine and is preferentially inhibited over Alr in M. tuberculosis.

Ethambutol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable arabinosyltransferase A (EMBA) [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Ethambutol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Mechanism Description: Ethambutol (EMB) is one of the first-line drugs regimens for TB treatment. Arabinosyl transferases are established targets of EMB, which is involved in the biosynthesis of arabinogalactan (AG) and lipoarabinomannan (LAM). Mutations among embCAB operon are responsible for around 70% clinical EMB resistant M. tuberculosis.

Key Molecule: Probable arabinosyltransferase B (EMBB) [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Ethambutol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Mechanism Description: Ethambutol (EMB) is one of the first-line drugs regimens for TB treatment. Arabinosyl transferases are established targets of EMB, which is involved in the biosynthesis of arabinogalactan (AG) and lipoarabinomannan (LAM). Mutations among embCAB operon are responsible for around 70% clinical EMB resistant M. tuberculosis.

Key Molecule: Probable arabinosyltransferase C (EMBC) [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Ethambutol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: STK11 KO cells; Fetal kidney; Homo sapiens (Human); CVCL_B3IE
• Mechanism Description: Ethambutol (EMB) is one of the first-line drugs regimens for TB treatment. Arabinosyl transferases are established targets of EMB, which is involved in the biosynthesis of arabinogalactan (AG) and lipoarabinomannan (LAM). Mutations among embCAB operon are responsible for around 70% clinical EMB resistant M. tuberculosis.

Isoniazid

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) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Isoniazid
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Isoniazid
• 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.

Perchlozone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [4]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [4]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [4]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [4]

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

Key Molecule: Enoyl-CoA hydratase 2 (HADA) [4]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Molecule Alteration: Frameshift mutation; c.13CGG > CCC (p.Arg > Pro)
• Resistant Drug: Perchlozone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain; 1313
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Mechanism Description: Perchlozone is a prodrug that is activated by EthA and inhibits the HadABC complex.A resistance to perchlozone was shown by in vitro experiments and was mediated by both ethA and hadA mutations.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Rifampin
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: Rifampin
• 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: Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis .J Antimicrob Chemother. 2017 Dec 1;72(12):3272-3276. doi: 10.1093/jac/dkx316. 10.1093/jac/dkx316
• Ref 2: Mycobacterial ethambutol responsive genes and implications in antibiotics resistance .J Drug Target. 2021 Mar;29(3):284-293. doi: 10.1080/1061186X.2020.1853733. Epub 2020 Dec 3. 10.1080/1061186X.2020.1853733
• Ref 3: 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
• Ref 4: Genetic Variation Putatively Associated with Mycobacterium tuberculosis Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis .Antibiotics (Basel). 2020 Oct 3;9(10):669. doi: 10.3390/antibiotics9100669. 10.3390/antibiotics9100669