Disease Information

General Information of the Disease (ID: DIS00017)

• Name: Leprosy
• ICD: ICD-11: 1B20

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  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]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Clofazimine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.T53A
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.P55R
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+poB p.S531L
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55S+rpoB p.S531L+rpoB p.V547I
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.A91V+gyrB p.A91V
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.D205N+gyrB p.D205N
• Resistant Drug: Clofazimine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Dapsone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.T53A
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.P55R
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+poB p.S531L
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55S+rpoB p.S531L+rpoB p.V547I
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.A91V+gyrB p.A91V
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.D205N+gyrB p.D205N
• Resistant Drug: Dapsone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Enoxacin

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]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Levofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Moxifloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+poB p.S531L
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55S+rpoB p.S531L+rpoB p.V547I
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.A91V+gyrB p.A91V
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.D205N+gyrB p.D205N
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.T53A
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.P55R
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+poB p.S531L
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA-directed RNA polymerase subunit beta (DHFR/RPOB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55S+rpoB p.S531L+rpoB p.V547I
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.A91V+gyrB p.A91V
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase/DNA gyrase subunit A/DNA gyrase subunit B (DHFR/GYRA/GYRB) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; folP p.P55L+gyrA p.D205N+gyrB p.D205N
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.T53A
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.P55R
• Resistant Drug: Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Sitafloxacin

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]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.D464N
• Resistant Drug: Sitafloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.N502D
• Resistant Drug: Sitafloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.E504V
• Resistant Drug: Sitafloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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

Dapsone/Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Molecule Alteration: Missense mutation; p.P55R
• Resistant Drug: Dapsone/Rifampin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

References

• Ref 1: Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. PLoS Negl Trop Dis. 2012;6(10):e1838. doi: 10.1371/journal.pntd.0001838. Epub 2012 Oct 11.
• Ref 2: Mutations in genes related to drug resistance in Mycobacterium leprae isolates from leprosy patients in Korea. J Infect. 2005 Jan;50(1):6-11. doi: 10.1016/j.jinf.2004.03.012.