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) 15 drug(s) in total

Amikacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Amikacin
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Capreomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CRISPR system Cms protein Csm4 (csm4) [2]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Capreomycin
• Molecule Alteration: Mutation; K444R/E+N450D
• In Vitro Model: L6TG Cap cells; N.A.; Homo sapiens (Human); CVCL_C566
• Experiment for Drug Resistance: MIC assay; Time-Kill assay
• Mechanism Description: We found that, the?rv2820c?K114N mutation was highly enriched in CAP-resistant?Mtb?clinical isolates, especially in those isolates with the known CAP resistance conferring mutation?rrs?A1401G, implying the association of this mutation with the antimycobacterial efficacy of CAP. Subsequently, over-expressing the?rv2820c?K114N mutant was shown to increase the tolerance to CAP in?Ms, implying that the?rv2820c?K114N mutation might also confer tolerance to CAP in?Mtb?and be considered as a potential molecular marker for CAP tolerance in?Mtb?clinical isolates.

Cycloserine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Alanine racemase (ALR) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Expression; Up-regulation
• 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) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Expression; Up-regulation
• 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) [3]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Missense mutation; p.C1030T
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ATP-binding cassette sub-family D member 1 (ABCD1) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Cycloserine
• Molecule Alteration: Mutation; rpsL gene at the 88th amino acid
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Delamanid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: FO synthase (FBIC) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Delamanid
• Molecule Alteration: Mutation; Q79K
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Ethambutol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Probable arabinosyltransferase A (EMBA) [5]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ethambutol
• Molecule Alteration: Mutation; .
• 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) [5]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ethambutol
• Molecule Alteration: Mutation; .
• 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) [5]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ethambutol
• Molecule Alteration: Mutation; .
• 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: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ethambutol
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Probable arabinosyltransferase B (EMBB) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ethambutol
• Molecule Alteration: Mutation; R173C
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Fluoroquinolones

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit B (GYRB) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Fluoroquinolones
• Molecule Alteration: Mutation; R658G
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Gentamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Gentamicin
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

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) [6]

• 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.

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Isoniazid
• Molecule Alteration: Expressiom; D96D
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [6]

• 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.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Expressiom; D1194A+R1181K+D1194G
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Perchlozone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [7]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [7]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [7]

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

Key Molecule: FAD-containing monooxygenase EthA (ETHA) [7]

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

Key Molecule: Enoyl-CoA hydratase 2 (HADA) [7]

• Resistant Disease: Multidrug-resistant tuberculosis [ICD-11: 1B10.2]
• Resistant Drug: Perchlozone
• Molecule Alteration: Frameshift mutation; c.13CGG > CCC (p.Arg > Pro)
• 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.

Pyrazinamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Pyrazinamidase/nicotinamidase (PncA) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Pyrazinamide
• Molecule Alteration: Mutation; Q859H/K
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Key Molecule: Small ribosomal subunit protein uS2 (RPSA) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Pyrazinamide
• Molecule Alteration: Mutation; rpoB gene
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Rifabutin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifabutin
• Molecule Alteration: Expressiom; D538G+Y537S+Y537N+E380Q
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase beta-subunit (rpoB) [8]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Mutations; Q24K+L28M+R30E+A92K
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: THP-1 cells; monocytic; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Microarray assay
• Experiment for Drug Resistance: Functional enrichment assay
• Mechanism Description: The overexpression of many interferon-stimulated genes (ISGs) in cells infected with the isoniazid-resistant strain, compared to the rifampin-resistant and the drug-sensitive strains.

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Enoyl-[acyl-carrier-protein] reductase [NADH] (INHA) [6]

• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [6]

• 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.

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Mutation; Q24K+L28M+R30E+A92K
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Mutation; R173C
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Rifapentine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Rifapentine
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: 30S ribosomal protein S12 (RPSL) [4]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Streptomycin
• Molecule Alteration: Mutation; Q24K+L28M+R30E+A92K
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: GeneSeq assay; Bioinformatics assay
• Mechanism Description: Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Sensitive Disease: Tuberculosis [ICD-11: 1B10.0]
• Sensitive Drug: Streptomycin
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

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

Topscience

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane protein A (OmpA) [1]

• Resistant Disease: Tuberculosis [ICD-11: 1B10.0]
• Resistant Drug: Topscience
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Mycobacterium tuberculosis; 1773
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.

References

• Ref 1: Overexpression of outer membrane protein A (OmpA) increases aminoglycoside sensitivity in mycobacteria. BMC Microbiol. 2024 Nov 13;24(1):472.
• Ref 2: The rv2820c K114N mutation is related with capreomycin tolerance. Tuberculosis (Edinb). 2024 Sep;148:102551.
• Ref 3: 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 4: Genetic diversities and drug resistance in Mycobacterium bovis isolates from zoonotic tuberculosis using whole genome sequencing. BMC Genomics. 2024 Nov 1;25(1):1024.
• Ref 5: 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 6: 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 7: Genetic Variation Putatively Associated with Mycobacterium tuberculosis Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis .Antibiotics (Basel). 2020 Oct 3;9(10):669. doi: 10.3390/antibiotics9100669. 10.3390/antibiotics9100669
• Ref 8: Differential Host Gene Expression in Response to Infection by Different Mycobacterium tuberculosis Strains-A Pilot Study. Microorganisms. 2024 Oct 25;12(11):2146.