Drug Information

Drug (ID: DG00092) and It's Reported Resistant Information

• Name: Nalidixic acid
• Synonyms: Betaxina; Cybis; Dixiben; Dixinal; Eucistin; Innoxalon; Jicsron; Kusnarin; Nalidicron; Nalidixan; Nalidixane; Nalidixate; Nalidixic; Nalidixin; Nalitucsan; Nalix; Nalurin; Narigix; Naxuril; NegGram; Negram; Nevigramon; Nicelate; Nogram; Poleon; Sicmylon; Specifen; Specifin; Unaserus; Uralgin; Uriben; Uriclar; Urisal; Urodixin; Uroman; Uroneg; Uronidix; Uropan; Wintomylon; Wintron; Acide nalidixico; Acide nalidixico [Italian]; Acide nalidixique; Acide nalidixique [French]; Acido nalidissico; Acido nalidissico [DCIT]; Acido nalidixico; Acidum nalidixicum; NALIDIXATE SODIUM; Naladixic acid; Naldixic acid; Nalidic acid; Nalidixinic acid; Nalidixic acid USP27; WIN 183203; Acid, Nalidixic; Acide nalidixique [INN-French]; Acido nalidixico [INN-Spanish]; Acidum nalidixicum [INN-Latin]; N-1200; NegGram (TN); Neggram (TN); Sodium Nalidixic Acid, Anhydrous; Sodium Nalidixic Acid, Monohydrate; Sodium,Nalidixate; WIN 18,320; WIN-18320; Wil 18,320; Wintomylon (TN); ZERO/002632; WIN-18320 (TN); Nalidixic acid (JP15/USP/INN); Nalidixic acid [USAN:INN:BAN:JAN]; Acide 1-etil-7-metil-1,8-naftiridin-4-one-3-carbossilico; Acide 1-etil-7-metil-1,8-naftiridin-4-one-3-carbossilico [Italian]; 1,4-Dihydro-1-ethyl-7-methyl-1,8-naphthyridin-4-one-3-carboxylic acid; 1,4-Dihydro-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; 1-Aethyl-7-methyl-1,8-naphthyridin-4-on-3-karbonsaeure; 1-Aethyl-7-methyl-1,8-naphthyridin-4-on-3-karbonsaeure [German]; 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxilic acid; 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; 1-Ethyl-7-methyl-1,4-dihydro-1,8-naphthyridin-4-one-3-carboxylic acid; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid; 1-ethyl-7-methyl-1,4-dihydro-1,8-naphthyridin-4-one-3-ca rboxylic acid; 1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; 3-Carboxy-1-ethyl-7-methyl-1,8-naphthidin-4-one; 3-Carboxy-1-ethyl-7-methyl-1,8-naphthyridin-4-one
• Indication:
  In total 1 Indication(s)
  Urinary tract infection [ICD-11: GC08]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (7 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  Cholera [ICD-11: 1A00]; [3]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [4]
  Gastroenteritis [ICD-11: 1A40]; [1], [5]
  Salmonellosis [ICD-11: 1A09]; [6]
  Shigellosis [ICD-11: 1A02]; [7]
  Typhoid fever [ICD-11: 1A07]; [1]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (3 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [8]
  Gram-negative bacterial infection [ICD-11: 1B74-1G40]; [9]
  Respiratory trac infection [ICD-11: CA45]; [10]
• Target: DNA topoisomerase II (TOP2); TOP2A_HUMAN TOP2B_HUMAN; [1]
• Formula: C12H12N2O3
• IsoSMILES: CCN1C=C(C(=O)C2=C1N=C(C=C2)C)C(=O)O
• InChI: 1S/C12H12N2O3/c1-3-14-6-9(12(16)17)10(15)8-5-4-7(2)13-11(8)14/h4-6H,3H2,1-2H3,(H,16,17)
• InChIKey: MHWLWQUZZRMNGJ-UHFFFAOYSA-N
• PubChem CID: 4421
• ChEBI ID: CHEBI:100147
• TTD Drug ID: D07JGT
• INTEDE ID: DR2296
• DrugBank ID: DB00779

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Cholera [ICD-11: 1A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA5, ereA2 lead to drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O26 strain AS482; 567107
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aadA1-S lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O62 strain AS438; 666
• In Vitro Model: Vibrio cholerae PG149a; 666
• In Vitro Model: Vibrio cholerae PG224; 666
• In Vitro Model: Vibrio cholerae PG262(b); 666
• In Vitro Model: Vibrio cholerae PG9; 666
• In Vitro Model: Vibrio cholerae PG95; 666
• In Vitro Model: Vibrio cholerae PL1; 666
• In Vitro Model: Vibrio cholerae PL61; 666
• In Vitro Model: Vibrio cholerae PL78/6; 666
• In Vitro Model: Vibrio cholerae PL91; 666
• In Vitro Model: Vibrio cholerae PG92; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA1 lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA15 lead to drug resistance.

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [2]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.S83L
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-112; 562
• In Vitro Model: Escherichia coli strain N-118; 562
• In Vitro Model: Escherichia coli strain N-119; 562
• In Vitro Model: Escherichia coli strain N-51; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.S83W
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-18; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.D87N
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-113; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.G81C
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-97; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.A84P
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-5; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.A67S
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain P-10; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Key Molecule: DNA gyrase subunit A (GYRA) [11], [12], [13]

• Molecule Alteration: Missense mutation; p.Q106H
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain kL16; 1425342
• In Vitro Model: Escherichia coli strain N-89; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Quinolones are considered to exert antibacterial activity by inhibiting DNA gyrase (EC 5.99.1.3), which catalyzes topological changes of DNA.DNA gyrase of Escherichia coli consists of subunits A and B, which are the products of the gyrA and gyrB genes, respectively. Mutations in either gene can cause quinolone resistance.

Shigellosis [ICD-11: 1A02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [7]

• Molecule Alteration: Missense mutation; p.A85T
• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• 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.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [7]

• Molecule Alteration: Missense mutation; p.D111H
• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• 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.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [7]

• Molecule Alteration: Missense mutation; p.S129P
• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [7]

• Molecule Alteration: Missense mutation; p.N57K
• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• 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.

Key Molecule: DNA gyrase subunit A (GYRA) [7]

• Molecule Alteration: Missense mutation; p.H80P
• Resistant Disease: Shigella intestinal infection [ICD-11: 1A02.0]
• 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.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [8]

• Molecule Alteration: Missense mutation; p.S80l
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ECIS803; 562
• In Vitro Model: Escherichia coli ATCC 43869; 562
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutational substitutions in the quinolone target enzymes, namely DNA topoisomerase II (GyrA) and topoisomerase IV (ParC), are recognised to be the major mechanisms through which resistance develops.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [8]

• Molecule Alteration: Missense mutation; p.E84G
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ECIS803; 562
• In Vitro Model: Escherichia coli ATCC 43869; 562
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutational substitutions in the quinolone target enzymes, namely DNA topoisomerase II (GyrA) and topoisomerase IV (ParC), are recognised to be the major mechanisms through which resistance develops.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [8]

• Molecule Alteration: Missense mutation; p.D476N
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ECIS803; 562
• In Vitro Model: Escherichia coli ATCC 43869; 562
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutational substitutions in the quinolone target enzymes, namely DNA topoisomerase II (GyrA) and topoisomerase IV (ParC), are recognised to be the major mechanisms through which resistance develops.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydropteroate synthase (SUL) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli Co227; 562
• In Vitro Model: Escherichia coli Co228; 562
• In Vitro Model: Escherichia coli Co232; 562
• In Vitro Model: Escherichia coli Co354; 562
• Experiment for Molecule Alteration: PCR; PCR-restriction fragment length polymorphism analysis; Sequencing assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Multiple-antibiotic-resistant phenotype is associated with gene mutation and mar locus regulation.

Typhoid fever [ICD-11: 1A07]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [1]

• Molecule Alteration: Missense mutation; p.W106G
• Resistant Disease: Typhoid fever [ICD-11: 1A07.0]
• 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.

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug export protein EmrA (EMRA) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of emrAB confers drug resistance.

Key Molecule: Multidrug export protein EmrB (EMRB) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of emrAB confers drug resistance.

Gastroenteritis [ICD-11: 1A40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit A (GYRA) [5], [1]

• Molecule Alteration: Missense mutation; p.S97P
• Resistant Disease: Gastroenteritis [ICD-11: 1A40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enteritidis isolates; 149539
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Quinolones target the bacterial DNA gyrase; this enzyme is a type II topoisomerase that is essential for bacterial DNA replication.This enzyme consists of 2A and 2B subunits encoded by gyrA and gyrB genes, respectively.

Key Molecule: DNA gyrase subunit A (GYRA) [5], [1]

• Molecule Alteration: Missense mutation; p.S83F
• Resistant Disease: Gastroenteritis [ICD-11: 1A40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enteritidis isolates; 149539
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Quinolones target the bacterial DNA gyrase; this enzyme is a type II topoisomerase that is essential for bacterial DNA replication.This enzyme consists of 2A and 2B subunits encoded by gyrA and gyrB genes, respectively.

Key Molecule: DNA gyrase subunit A (GYRA) [5], [1]

• Molecule Alteration: Missense mutation; p.D87Y
• Resistant Disease: Gastroenteritis [ICD-11: 1A40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enteritidis isolates; 149539
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Quinolones target the bacterial DNA gyrase; this enzyme is a type II topoisomerase that is essential for bacterial DNA replication.This enzyme consists of 2A and 2B subunits encoded by gyrA and gyrB genes, respectively.

Key Molecule: DNA gyrase subunit A (GYRA) [5], [1]

• Molecule Alteration: Missense mutation; p.D87N
• Resistant Disease: Gastroenteritis [ICD-11: 1A40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enteritidis isolates; 149539
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: Quinolones target the bacterial DNA gyrase; this enzyme is a type II topoisomerase that is essential for bacterial DNA replication.This enzyme consists of 2A and 2B subunits encoded by gyrA and gyrB genes, respectively.

Gram-negative bacterial infection [ICD-11: 1B74-1G40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [9]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli k-12 BW25113; 679895
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: OM proteins, a unique OM component of Gram-negative bacteria, constitute a barrier against large hydrophilic and lipophilic molecules and therefore play an important role in stress responses to drugs, osmotic pressure and acids.MipA is a novel OM protein related to antibiotic resistance.MipA expression was up-regulated in kanamycin-resistant,Au-R and Cm-R strains and down-regulated in NA-R and Str-R strains.

ICD-12: Respiratory system diseases

Respiratory trac infection [ICD-11: CA45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [10]

• Molecule Alteration: Missense mutation; p.S80L
• Resistant Disease: Respiratory trac infection [ICD-11: CA45.0]
• 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.

References

• Ref 1: 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 2: New aminoglycoside acetyltransferase gene, aac(3)-Id, in a class 1 integron from a multiresistant strain of Vibrio fluvialis isolated from an infant aged 6 months. J Antimicrob Chemother. 2004 Jun;53(6):947-51. doi: 10.1093/jac/dkh221. Epub 2004 Apr 29.
• Ref 3: Occurrence of antibiotic resistance gene cassettes aac(6')-Ib, dfrA5, dfrA12, and ereA2 in class I integrons in non-O1, non-O139 Vibrio cholerae strains in India. Antimicrob Agents Chemother. 2002 Sep;46(9):2948-55. doi: 10.1128/AAC.46.9.2948-2955.2002.
• Ref 4: Mechanisms of resistance in multiple-antibiotic-resistant Escherichia coli strains of human, animal, and food origins. Antimicrob Agents Chemother. 2004 Oct;48(10):3996-4001. doi: 10.1128/AAC.48.10.3996-4001.2004.
• Ref 5: Prevalence of gyrA Mutations in Nalidixic Acid-Resistant Strains of Salmonella Enteritidis Isolated from Humans, Food, Chickens, and the Farm Environment in Brazil. Microb Drug Resist. 2017 Jun;23(4):421-428. doi: 10.1089/mdr.2016.0024. Epub 2016 Aug 25.
• Ref 6: Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol Microbiol. 2006 Jan;59(1):126-41. doi: 10.1111/j.1365-2958.2005.04940.x.
• Ref 7: 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 8: Characterisation of novel mutations involved in quinolone resistance in Escherichia coli isolated from imported shrimp. Int J Antimicrob Agents. 2015 May;45(5):471-6. doi: 10.1016/j.ijantimicag.2014.11.010. Epub 2015 Jan 13.
• Ref 9: Outer membrane proteomics of kanamycin-resistant Escherichia coli identified MipA as a novel antibiotic resistance-related protein. FEMS Microbiol Lett. 2015 Jun;362(11):fnv074. doi: 10.1093/femsle/fnv074. Epub 2015 May 3.
• 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.
• Ref 11: 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother. 1991 Feb;35(2):387-9. doi: 10.1128/AAC.35.2.387.
• Ref 12: Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother. 1990 Jun;34(6):1271-2. doi: 10.1128/AAC.34.6.1271.
• Ref 13: Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother. 1989 Jun;33(6):886-94. doi: 10.1128/AAC.33.6.886.