Disease Information

General Information of the Disease (ID: DIS00033)

• Name: HIV associated with tuberculosis
• ICD: ICD-11: 1C60

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

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 9 drug(s) in total

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.N538D
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.E540V
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Co-trimoxazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Resistant Disease: HIV-infected Pneumocystis pneumonia [ICD-11: 1C60.1]
• Molecule Alteration: Missense mutation; p.V96I
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii isolates; 42068
• Experiment for Molecule Alteration: nested PCR
• Mechanism Description: Among the 76 enrolled HIV-positive patients, only 17 (22.4%) were positive for P. jirovecii. DHPS gene sequencing showed a novel nucleotide substitution at position 288 (Val96Ile) in three patients (3/12; 25.0%). Patients infected with the mutant P. jirovecii genotype had severe episodes of PCP, did not respond to SXT and had a fatal outcome.

Copper

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Copper-translocating P-type ATPase (COPA) [4]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Copper
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: Mycobacterium smegmatis mc2155; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155-Cu; 246196
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Quantitative proteomics was carried out to find differentially expressed proteins between mc2155 and mc2155-Cu. Among 345 differentially expressed proteins, copper-translocating P-type ATPase was up-regulated, while all other ABC transporters were down-regulated in mc2155-Cu, suggesting copper-translocating P-type ATPase plays a crucial role in copper resistance. Results also indicated that the down-regulation of metabolic enzymes and decreases in cellular NAD, FAD, mycothiol, and glutamine levels in mc2155-Cu were responsible for its slowing growth rate as compared to mc2155.

Isoniazid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Catalase-peroxidase (KATG) [4]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: Mycobacterium smegmatis mc2155; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155-Cu; 246196
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: As a prodrug, INH needs to be activated by katG to execute its antibiotic function. katG is a bifunctional enzyme with both catalase and peroxidase activity and catalyzes the coupling of INH with NAD+ to form the isonicotinic acyl-NAD complex, which binds to the enoyl-acyl carrier protein reductase to inhibit the synthesis of mycolic acid required for the mycobacterial cell wall. In the present study, quantitative proteomic analysis showed that the expression level of katG was down-regulated in mc2155-Cu as compared to mc2155. Down-regulation of katG expression as well as a decrease in cellular NAD level results in the higher resistance to INH in mc2155-Cu.

Key Molecule: Arylamine N-acetyltransferase 1 (NAT1) [5]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Titertek multiskan assay
• Mechanism Description: Arylamine N-acetyltransferase (NAT), a drug-metabolizing enzyme of MTB, can acetylate INH, transferring an acetyl group from acetyl coenzyme A to the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The overexpression of NAT in Mycobacterium smegmatis showed increased resistance to INH; in addition, when the gene was knocked-out, the bacteria exhibited increased sensitivity to INH.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Isocitrate lyase 1 (ICL1) [6]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

Key Molecule: Isocitrate lyase 2 (ICL2) [6]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Isocitrate lyase 1 (ICL1) [6]

• Sensitive Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

Key Molecule: Isocitrate lyase 2 (ICL2) [6]

• Sensitive Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Isoniazid
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

Levofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.N538D
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Moxifloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.N538D
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.E540D
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.N538D
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Ribonuclease PH (RPH) [7], [8], [9]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Bacillus cereus RPH-Bc; 1396
• In Vitro Model: Escherichia coli Rosetta(DE3) pLysS; 866768
• In Vitro Model: L. monocytogenes; 1639
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: RIF phosphotransferase (rph) led to the identification of a new resistance gene and associated enzyme responsible for inactivating rifamycin antibiotics by phosphorylation.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.L511P
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.Q513P
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.Q513K
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.D516V
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526N+p.L533P
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526Y
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526R
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526D
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526N
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526L
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.H526C
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.S531W
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.S531L
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.L533P
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.E562G+p.P564L
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [10], [11], [12]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Frameshift mutation; c.513_516del*AA TTC ATG G*
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: More than 96% of rifampicin-resistant strains show mutations in a portion of the RNA polymerase B subunit gene (rpoB), called the hot-spot region, encompassing codons 507-533.Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Uncharacterized MFS-type transporter EfpA (EFPA) [13], [14], [15]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis H37Rv; 83332
• In Vitro Model: Mycobacterium tuberculosis MTB1; 1773
• In Vitro Model: Mycobacterium tuberculosis MTB2; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The induced strains presented an increased efflux activity that was inhibited by the efflux inhibitors (EIs) and showed overexpression of the efflux pump genes efpA, mmpL7, mmr, p55 and the Tap-like gene Rv1258c. Altogether, these results correlate efflux activity with INH resistance and demonstrate that efflux pumps play an important role in acquired INH resistance in M. tuberculosis complex.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Probable arabinosyltransferase B (EMBB) [16]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Missense mutation; p.M306I
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Test for drug susceptibility in L-J medium assay
• Mechanism Description: An embB mutation has a strong relationship to rifampin resistance. Inhibition of cell wall biosynthesis may not play an important role, and inhibition of RNA metabolism may be partly responsible.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 30S ribosomal protein S12 (RPSL) [17], [18], [19]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Molecule Alteration: Mutantion; p.K43R+p.K88Q+p.K88R
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium tuberculosis strain; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Mycobacterium tuberculosis is associated either with missense mutations in the rpsL gene, which encodes ribosomal protein S12, or with base substitutions at position 904 in the 16S rRNA.Streptomycin resistant isolates harbored mutations in rpsL (codons k43R, k88Q, k88R) and rrs (nucleotide A514C).

References

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