Molecule Information

General Information of the Molecule (ID: Mol00935)

• Name: DNA topoisomerase 4 subunit A (PARC) ,Morganella morganii
• Synonyms: Topoisomerase IV subunit A; SAMN05216301_3029
• Molecule Type: Protein
• Gene Name: parC
• Sequence:
  MSEITHDGVERQALHNFTENAYLNYSMYVIMDRALPFIGDGLKPVQRRIVYAMSELGLSN
  SAKYKKSARTVGDVLGKYHPHGDSACYEAMVLMAQPFSYRYPLVDGQGNWGAPDDPKSFA
  AMRYTESRLSKYAEVLLSELGHGTADWVPNFDGTMQEPKMLPARLPNILLNGTTGIAVGM
  ATDIPPHNAREVTGALLALIDKPSLSLEDVMAFIPGPDYPTEAEIITGPEDIRKIYKSGR
  GSVRMRAVWTIEDGNAVITALPHQVSGAKVLEQIAAQMRAKKLPMVEDLRDESDHENPTR
  LVVVPRSNRIDLDQVMTHLFATTDLERSYRINLNMIGLDGRPAVKGLVEILNEWLVYRRE
  TVRRRLNHRLEKVLRRLHILDGLLLAYLNIDEVIDIIRSEDEPKPVLMDRFGLSDTQAEA
  ILELKLRHLAKLEEMKIRGEQDELAKERDKLQAILGSERRMNTLLKKELEEDAKQYGDDR
  RSPLNEREEAKAMSEHDILPSEPLTVVLSQMGWVRSAKGHDIDPAGMNYKAGDSFLGAAR
  GKSNQPVVFLDSTGRSYSLDPLELPGARGQGEPLTGKLTPPPGAVFEQVLMNDENQKYLM
  ASDAGYGFICTFSDLVAKNKAGKVLITLPDNAKVMTPIEVNDEENDLLLAVSQEGRMLLF
  PVGDLPQLSKGKGNKIISITSAAAAAGEDGLAHLFVIRPDASVTLHFGKRKLMLRPEDLQ
  KFRAERGRRGTALPRGMQKKIERIDISEPEPKA
• 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: A0A1M7LLM7_MORMO

Kingdom: N.A.
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Enterobacterales
Family: Morganellaceae
Genus: Morganella
Species: Morganella morganii

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) 7 drug(s) in total

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Gonococcal infection [1], [2]

• Resistant Disease: Gonococcal infection [ICD-11: 1A70.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.E91G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Neisseria gonorrhoeae isolates; 485
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Fluoroquinolones block DNA replication by inhibiting the enzymes DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase catalyzes the untwisting of DNA molecules during DNA replication, and consists of two type A subunits and two type B subunits encoded by gyrA and gyrB genes. Topoisomerase IV consists of two type C subunits and two type E subunits encoded by parC and parE genes.GyrA S91F, D95G/D95A and ParC E91G amino acid substitutions mediate high fluoroquinolone resistance in the analyzed kenyan GC.

Disease Class: Bacterial infection [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Disease Class: Nongonococcal urethritis [4], [5]

• Resistant Disease: Nongonococcal urethritis [ICD-11: 1A81.3]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83W
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Nongonococcal urethritis [4], [5]

• Resistant Disease: Nongonococcal urethritis [ICD-11: 1A81.3]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83P
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Nongonococcal urethritis [4], [5]

• Resistant Disease: Nongonococcal urethritis [ICD-11: 1A81.3]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; ParC p.S83L+GyrB p.P462S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Miscarriage [4], [5]

• Resistant Disease: Miscarriage [ICD-11: JA00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83W
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Miscarriage [4], [5]

• Resistant Disease: Miscarriage [ICD-11: JA00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83P
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Miscarriage [4], [5]

• Resistant Disease: Miscarriage [ICD-11: JA00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; ParC p.S83L+GyrB p.P462S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Preterm delivery with lung infection in neonates [4], [5]

• Resistant Disease: Preterm delivery with lung infection in neonates [ICD-11: JB00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83W
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Preterm delivery with lung infection in neonates [4], [5]

• Resistant Disease: Preterm delivery with lung infection in neonates [ICD-11: JB00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S83P
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Preterm delivery with lung infection in neonates [4], [5]

• Resistant Disease: Preterm delivery with lung infection in neonates [ICD-11: JB00.0]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; ParC p.S83L+GyrB p.P462S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12 JM109; 83333
• In Vitro Model: Ureaplasma parvum serovar 3 isolates; 38504
• In Vitro Model: Ureaplasma parvum serovar 6 isolates; 95660
• In Vitro Model: Ureaplasma urealyticum isolates; 2130
• In Vitro Model: Ureaplasma parvum isolates; 38504
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolones are used for treating urogenital infections and interact in bacteria with the type II topoisomerases DNA gyrase and topoisomerase IV, both of which are composed of two A and two B subunits; these subunits are encoded by the gyrA and gyrB genes for DNA gyrase and parC and parE genes for topoisomerase IV.Out of 28 clinical Ureaplasma strains, we isolated 9 with high MICs of quinolones and found a single parC gene mutation, resulting in the change S83L.

Disease Class: Bacterial infection [6]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S80I
• 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: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Ciprofloxacin XR
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Levofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Bacterial infection [3]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.S83L; p.S80L
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• Experiment for Molecule Alteration: ERIC-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Mutations that occur in gyrA and parC genes were detected by DNA sequence analysis in 16 resistant strains representing each clone and subtype.

Disease Class: Bacterial infection [6]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Levofloxacin
• Molecule Alteration: Missense mutation; p.S80I
• 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.

Nalidixic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Typhoid fever [8]

• Resistant Disease: Typhoid fever [ICD-11: 1A07.0]
• Resistant Drug: Nalidixic acid
• Molecule Alteration: Missense mutation; p.W106G
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica subsp. enterica serovar Typhi isolates; 90370
• Experiment for Molecule Alteration: PCR-RFLP
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The targets of fluoroquinolones are the two enzymes, DNA gyrase and topoisomerase IV, whose subunits are encoded respectively by gyrA and gyrB and the parC and parE genes.The alteration caused by single point mutations within the QRDR of the DNA gyrase subunit gyrA gene leads to quinolone resistance.

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Nalidixic acid
• Molecule Alteration: Missense mutation; p.A85T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Nalidixic acid
• Molecule Alteration: Missense mutation; p.D111H
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Nalidixic acid
• Molecule Alteration: Missense mutation; p.S129P
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Respiratory trac infection [10]

• Resistant Disease: Respiratory trac infection [ICD-11: CA45.0]
• Resistant Drug: Nalidixic acid
• Molecule Alteration: Missense mutation; p.S80L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Quinolone/fluoroquinolone resistance is most likely due to mutations in the genes gyrA and parC encoding DNA gyrase and topoisomerase IV.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.A85T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.D111H
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Shigella intestinal infection [9]

• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.S129P
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Escherichia coli ATCC 35218; 562
• In Vitro Model: Shigella flexneri isolates; 623
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Disk diffusion test assay
• Mechanism Description: Mutations Asn57Lys and His80Pro in gyrA and Ala85Thr, Asp111His and Ser129Pro in parC. induce fluoroquinolone resistance with a significantly high mutation rate of the gyrA and parC genes in S. flexneri.

Disease Class: Bacterial infection [6]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Norfloxacin
• Molecule Alteration: Missense mutation; p.S80I
• 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.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Bacterial infection [6]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.S80I
• 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.

Pefloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pefloxacin
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pefloxacin
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Pefloxacin
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Sparfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Sparfloxacin
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Sparfloxacin
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: Sparfloxacin
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

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

PD131628

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: PD131628
• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: PD131628
• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Disease Class: Pneumocystis jirovecii infection [7]

• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Resistant Drug: PD131628
• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

References

• Ref 1: Molecular epidemiology of drug-resistant Neisseria gonorrhoeae in Russia (Current Status, 2015). BMC Infect Dis. 2016 Aug 9;16:389. doi: 10.1186/s12879-016-1688-7.
• Ref 2: gyrA and parC mutations in fluoroquinolone-resistant Neisseria gonorrhoeae isolates from Kenya. BMC Microbiol. 2019 Apr 8;19(1):76. doi: 10.1186/s12866-019-1439-1.
• Ref 3: [Investigation of fluoroquinolone resistance mechanisms in clinical Acinetobacter baumannii isolates]. Mikrobiyol Bul. 2016 Apr;50(2):278-86. doi: 10.5578/mb.24126.
• Ref 4: In vitro activity of five quinolones and analysis of the quinolone resistance-determining regions of gyrA, gyrB, parC, and parE in Ureaplasma parvum and Ureaplasma urealyticum clinical isolates from perinatal patients in Japan. Antimicrob Agents Chemother. 2015 Apr;59(4):2358-64. doi: 10.1128/AAC.04262-14. Epub 2015 Feb 2.
• Ref 5: Analysis of mutations in DNA gyrase and topoisomerase IV of Ureaplasma urealyticum and Ureaplasma parvum serovars resistant to fluoroquinolones. Infect Genet Evol. 2017 Jan;47:64-67. doi: 10.1016/j.meegid.2016.11.019. Epub 2016 Nov 21.
• Ref 6: 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 7: Contribution of mutations in gyrA and parC genes to fluoroquinolone resistance of mutants of Streptococcus pneumoniae obtained in vivo and in vitro. Antimicrob Agents Chemother. 1996 Nov;40(11):2505-10. doi: 10.1128/AAC.40.11.2505.
• Ref 8: GyrA ser83 and ParC trp106 Mutations in Salmonella enterica Serovar Typhi Isolated from Typhoid Fever Patients in Tertiary Care Hospital. J Clin Diagn Res. 2016 Jul;10(7):DC14-8. doi: 10.7860/JCDR/2016/17677.8153. Epub 2016 Jul 1.
• Ref 9: Novel mutations in quinolone resistance-determining regions of gyrA, gyrB, parC and parE in Shigella flexneri clinical isolates from eastern Chinese populations between 2001 and 2011. Eur J Clin Microbiol Infect Dis. 2016 Dec;35(12):2037-2045. doi: 10.1007/s10096-016-2761-2. Epub 2016 Sep 12.
• Ref 10: Topoisomerase mutations that are associated with high-level resistance to earlier fluoroquinolones in Staphylococcus aureus have less effect on the antibacterial activity of besifloxacin. Chemotherapy. 2011;57(5):363-71. doi: 10.1159/000330858. Epub 2011 Oct 12.