Molecule Information

General Information of the Molecule (ID: Mol00936)

• Name: DNA topoisomerase 4 subunit B (PARE) ,Bartonella bacilliformis
• Synonyms: Topoisomerase IV subunit B; gyrB; BARBAKC583_0899
• Molecule Type: Protein
• Gene Name: parE
• Sequence:
  MSNDNKDLFSVLNHAQSRIDRKENTQYTSAHSEIVVPAVPLSSPHHHKEDSTYNASSIRI
  LEGLEPVRLRPGMYIGGTDSKALHHLFSEIIDNAMDEAVAGYADLIDITLDSNNYLTVTD
  NGRGIPIENHPQIPDKSTLEVIMTHLHSGGKFDGKAYQTSGGLHGVGISVVNALSDDMEV
  EVARERKLYRQRFSRGIPQSGLEELGDVYNRRGTRVCFHPDSQIFGENTAFDPEKIYKIA
  RSKAYLFNGVKIRWNCDPAALKDAKNIPEKDVFYFPDGLKDYLSLSLKNKHLVTAEIFSG
  KTQQLSGHGSVEWAIAWHNGDAYIQSYCNTIPTEEGGTHETGLRQTLLRGLKAYAELIGN
  KRASIITSDDVMASTVVMLSVFIKDPQFVGQTKDRLATTEAQRIVENAIRDPFDHWLANS
  PHEATKLLNWVIERAEERLKRRQDREINRKTAVRKLRLPGKLADCSQNSAAGAELFIVEG
  DSAGGSAKQARNRTNQAILPLRGKILNVASAAREKMSSSQTIADLILALGCGTRSKYREE
  DLRYERIIIMTDADVDGAHIASLLITFFFQEIPDLIRAGHLYLAVPPLYRISQGGKVAYA
  RDDSHKDELLKTEFTGKGKIEIGRFKGLGEMRAEQLKETTMNPKKRTLLRVSIDTFEMQE
  TKETVQNLMGTKPEERFRFIQESSTFANNLDI
• Function: Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.
• Uniprot ID: PARE_BARBK

Kingdom: N.A.
Phylum: Proteobacteria
Class: Alphaproteobacteria
Order: Hyphomicrobiales
Family: Bartonellaceae
Genus: Bartonella
Species: Bartonella bacilliformis

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Approved Drug(s) 8 drug(s) in total

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.N538D
• 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.

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.E540V
• 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.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S463A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S464Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.E504V
• 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.

Enoxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Enoxacin
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Enoxacin
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Enoxacin
• Molecule Alteration: Missense mutation; p.E504V
• 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)

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.N538D
• 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.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.S463A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.S464Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.E504V
• 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)

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Moxifloxacin
• Molecule Alteration: Missense mutation; p.N538D
• 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.

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Moxifloxacin
• Molecule Alteration: Missense mutation; p.E540D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Moxifloxacin
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Moxifloxacin
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Moxifloxacin
• Molecule Alteration: Missense mutation; p.E504V
• 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.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.S463A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.S464Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Novobiocin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Staphylococcus aureus infection [5]

• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Resistant Drug: Novobiocin
• Molecule Alteration: Missense mutation; p.A89G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

Disease Class: Staphylococcus aureus infection [5]

• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Resistant Drug: Novobiocin
• Molecule Alteration: Missense mutation; p.S128L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: HIV-infected patients with tuberculosis [1], [2]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.N538D
• 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.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.S463A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Morganella morganii infection [3]

• Resistant Disease: Morganella morganii infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.S464Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Morganella morganii isolate; 582
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutations in DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC,parE) genes result in quinolone susceptibility.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.E504V
• 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.

Sitafloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Sitafloxacin
• Molecule Alteration: Missense mutation; p.D464N
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Sitafloxacin
• Molecule Alteration: Missense mutation; p.N502D
• 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.

Disease Class: Leprosy [4]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Sitafloxacin
• Molecule Alteration: Missense mutation; p.E504V
• 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

Coumermycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Bartonella bacilliformis infection [6]

• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Resistant Drug: Coumermycin
• Molecule Alteration: Missense mutation; p.G124S
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Disease Class: Bartonella bacilliformis infection [6]

• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Resistant Drug: Coumermycin
• Molecule Alteration: Missense mutation; p.R184Q
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Disease Class: Bartonella bacilliformis infection [6]

• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Resistant Drug: Coumermycin
• Molecule Alteration: Missense mutation; p.Y214A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Disease Class: Bartonella bacilliformis infection [6]

• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Resistant Drug: Coumermycin
• Molecule Alteration: Missense mutation; p.Y214I
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

References

• Ref 1: Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother. 2006 Jan;50(1):104-12. doi: 10.1128/AAC.50.1.104-112.2006.
• Ref 2: New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLoS One. 2012;7(6):e39754. doi: 10.1371/journal.pone.0039754. Epub 2012 Jun 28.
• Ref 3: Type II and type IV topoisomerase mutations in clinical isolates of Morganella morganii harbouring the qnrD gene. Ann Clin Microbiol Antimicrob. 2014 Aug 9;13:34. doi: 10.1186/s12941-014-0034-4.
• Ref 4: 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 5: Accumulation of mutations in both gyrB and parE genes is associated with high-level resistance to novobiocin in Staphylococcus aureus. Antimicrob Agents Chemother. 2005 Sep;49(9):3810-5. doi: 10.1128/AAC.49.9.3810-3815.2005.
• Ref 6: Mutations in Bartonella bacilliformis gyrB confer resistance to coumermycin A1. Antimicrob Agents Chemother. 1998 Nov;42(11):2906-13. doi: 10.1128/AAC.42.11.2906.