Disease Information

General Information of the Disease (ID: DIS00003)

• Name: Escherichia coli intestinal infection
• ICD: ICD-11: 1A03

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 40 drug(s) in total

Amikacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Amikacin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: The resistant strains contained an identical 6.8-kilobase plasmid, pRPG101. Transformation of pRPG101 into Escherichia coli produced high-level resistance to amikacin (greater than or equal to 256 micrograms/ml) and kanamycin (greater than or equal to 256 micrograms/ml) but unchanged susceptibilities to gentamicin, netilmicin, and tobramycin. The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [5]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Acinetobacter baumannii strain BM2580; 470
• In Vitro Model: Bacillus subtilis strain BS168; 1423
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The shuttle piasmid pAT239 was constructed by inserting the H/ndlll-linearized staphyococcal piasmid pC194 into the unique H/ndlll site of pAT235. This piasmid, which confers resistance to ampicillin, chloramphenicol and kanamycin in Escherichia coli, was introduced by transformation into Bacillus subtilis strain BS168.

Ampicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• 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 Co356; 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.

Key Molecule: Beta-lactamase (BLA) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• 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 Co356; 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.

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Key Molecule: Beta-lactamase (BLA) [7]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain JC2926; 562
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: SHV Beta-lactamases confer resistance to a broad spectrum of Beta-lactam antibiotics and are of great therapeutic concern for infections caused by many species of the family Enterobacteriaceae. SHV-1, the original member of the SHV Beta-lactamase family, is present in most strains of Klebsiella pneumoniae and may be either chromosomally or plasmid mediated. A plasmid-mediated SHV-1 is also commonly found in Escherichia coli and is seen in other genera as well.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [8]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli strain JM103; 83333
• In Vitro Model: Bacillus circulans strain; 1397
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Streptomyces lividans strain M180; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Semi-quantitative phosphocellulose-paper binding assay method assay
• Mechanism Description: The previous demonstration that the APH gene of B. circulans could be expressed in E.coli. These contained a 5.5kb Hind3-digest insert (pCH4) or a 2.7kb Sal1-digest insert (pCH5) at the corresponding site in pBR322. Both these derivatives expressed ampicillin and ribostamycin resistance in E.coli.

Aztreonam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Aztreonam
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Bacitracin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Bacitracin F

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Bacitracin methylene disalicylate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin methylene disalicylate
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [9]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Bacitracin methylene disalicylate
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Cefepime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cefepime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Outer membrane porin F (OMPF) [10]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G119D
• Resistant Drug: Cefepime
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterobacter cloacae strain 201-RevM3; 550
• In Vitro Model: Escherichia coli strain Ak101; 562
• In Vitro Model: Escherichia coli strain BZB1107; 562
• In Vitro Model: Escherichia coli strain DH5alpha mutS; 668369
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size.

Key Molecule: Outer membrane porin F (OMPF) [10]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G119E
• Resistant Drug: Cefepime
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterobacter cloacae strain 201-RevM3; 550
• In Vitro Model: Escherichia coli strain Ak101; 562
• In Vitro Model: Escherichia coli strain BZB1107; 562
• In Vitro Model: Escherichia coli strain DH5alpha mutS; 668369
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size.

Cefotaxime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Cefotaxime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Ceftazidime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Key Molecule: Beta-lactamase (BLA) [12]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterobacter cloacae strains ENLA-1; 550
• In Vitro Model: Escherichia coli strain ECAA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-2; 562
• In Vitro Model: Escherichia coli strain ECLA-4; 562
• In Vitro Model: Escherichia coli strain ECZK-1; 562
• In Vitro Model: Escherichia coli strain ECZP-1; 562
• In Vitro Model: Escherichia coli strain ECZU-1; 562
• In Vitro Model: Escherichia coli strain HK225f; 562
• In Vitro Model: Klebsiella pneumoniae strains KPAA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPBE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-3; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-5; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-9; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-11; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-12; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-13; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-9; 573
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-1; 149384
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-2; 149384
• Experiment for Molecule Alteration: Hybridization experiments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Of 60 strains with reduced susceptibility to expanded-spectrum cephalosporins which had been collected, 34 (24Klebsiella pneumoniae, 7Escherichia coli, 1Enterobacter cloacae, and 2Salmonella entericaserotypewien) hybridized with the intragenic blaSHVprobe. TheblaSHVgenes were amplified by PCR, and the presence ofblaSHV-ESBLwas established in 29 strains by restriction enzyme digests of the resulting 1,018-bp amplimers as described elsewhere. These results were confirmed by the nucleotide sequencing of all 34 amplimers. Five strains contained SHV non-ESBL enzymes.

Ceftriaxone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Key Molecule: Beta-lactamase (BLA) [12]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ceftriaxone
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterobacter cloacae strains ENLA-1; 550
• In Vitro Model: Escherichia coli strain ECAA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-1; 562
• In Vitro Model: Escherichia coli strain ECLA-2; 562
• In Vitro Model: Escherichia coli strain ECLA-4; 562
• In Vitro Model: Escherichia coli strain ECZK-1; 562
• In Vitro Model: Escherichia coli strain ECZP-1; 562
• In Vitro Model: Escherichia coli strain ECZU-1; 562
• In Vitro Model: Escherichia coli strain HK225f; 562
• In Vitro Model: Klebsiella pneumoniae strains KPAA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPBE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPGE-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-2; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-3; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-5; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPLA-9; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-1; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-10; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-11; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-12; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-13; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-4; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-6; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-7; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-8; 573
• In Vitro Model: Klebsiella pneumoniae strains KPZU-9; 573
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-1; 149384
• In Vitro Model: Salmonella enterica serotype wien strain SWLA-2; 149384
• Experiment for Molecule Alteration: Hybridization experiments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: Of 60 strains with reduced susceptibility to expanded-spectrum cephalosporins which had been collected, 34 (24Klebsiella pneumoniae, 7Escherichia coli, 1Enterobacter cloacae, and 2Salmonella entericaserotypewien) hybridized with the intragenic blaSHVprobe. TheblaSHVgenes were amplified by PCR, and the presence ofblaSHV-ESBLwas established in 29 strains by restriction enzyme digests of the resulting 1,018-bp amplimers as described elsewhere. These results were confirmed by the nucleotide sequencing of all 34 amplimers. Five strains contained SHV non-ESBL enzymes.

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: CATB6 chloramphenicol acetyltransferase (CATB6) [13]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Pseudomonas aeruginosa strain 101/1477; 287
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Broth microdilution assay
• Mechanism Description: The third gene cassette is 730 bp long and contains an open reading frame (ORF) potentially encoding a protein that exhibits a high degree of sequence similarity to members of the CATB lineage of chloramphenicol acetyltransferases. The new catB allele appeared to be functional since both DH5alpha(pPAM-101) and DH5alpha(pkAM-36BE) showed a decreased chloramphenicol susceptibility and was named catB6.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [14]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain k12; 83333
• In Vitro Model: Escherichia coli strain JM111; 83333
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: Enzymic acetylation catalysed by chloramphenicol acetyltransferase is the commonest mechanism of bacterial resistance to the antibiotic chloramphenicol, an inhibitor of prokaryotic peptidyl-transferase activity.

Key Molecule: Chloramphenicol acetyltransferase 2 (CATII) [15]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM 101; 562
• Mechanism Description: Bacterial resistance to the antibiotic chloramphenicol, an inhibitor of the peptidyltransferase activity of prokaryotic ribosomes, is commonly conferred by the enzyme chloramphenicol acetyltransferase (CAT,EC2.3.1.28). The enzyme catalyses transfer of the acetyl group of acetyl-CoA to the primary (C-3) hydroxy group of chloramphenicol, yielding 3-acetylchloramphenicol, which fails to bind to bacterial ribosomes. Three classes of CAT variant have been characterized among Gram-negative bacteria, designated typesI, II and III.

Key Molecule: Chloramphenicol acetyltransferase (CAT) [16]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Chloramphenicol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain XL-1 Blue; 562
• In Vitro Model: A Staphylococcus intermedius strain isolated from a purulent skin infection of a dog; 1285
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Mechanism Description: Subsequently, Escherichia coli XL-1 blue cells transformed with these recombinant plasmids were tested for CmR. In one orientation, Escherichia coli XL-1 blue demonstrated CmR at 15 ug/ml Cm while in the other orientation a higher level of CmR occurred (80 ug/m Cm).

Key Molecule: Chloramphenicol acetyltransferase (CAT) [17]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: Nucleotide sequence assay
• Mechanism Description: Bacterial resistance to chloramphenicol is most commonly mediated by production of the enzyme chloramphenicol acetyltransferase (CAT), which catalyzes the transfer of an acetyl group from acetyl coenzyme A to the primary hydroxyl group of chloramphenicol (O-acetylation). The O-acetoxy derivatives of chloramphenicol do not bind to bacterial ribosomes and are consequently devoid of antimicrobial activity. Recombinant strains were derivatives of Escherichia coli DH5alpha and were grown in 2YT medium supplemented with ampicillin (100 ug/ml) and chloramphenicol (30 ug/ml) where appropriate. Cloning experiments conducted in this study utilized the Escherichia coli plasmid vector pUC18.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Dipeptide and tripeptide permease A (DTPA) [18]

• Sensitive Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Chloramphenicol
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Escherichia coli BL21(DE3)pLysS cell; 866768
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Determination of MICs assay
• Mechanism Description: POT YdgR facilitates Cam uptake in E. coli.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.D476N
• Resistant Drug: Ciprofloxacin XR
• 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.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [11]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• Experiment for Molecule Alteration: PCR and molecular characterization assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: CTX-M-55 is a novel ceftazidime-resistant CTX-M extended-spectrum Beta-lactamase, which reduced susceptibility.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.S80l
• Resistant Drug: Ciprofloxacin XR
• 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) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.E84G
• Resistant Drug: Ciprofloxacin XR
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone resistance protein NorA (NORA) [20]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Staphylococcus aureus strain SA113; 1280
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Mechanism Description: The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus Tk2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. Escherichia coli strains containing one of the plasmids carrying the norA gene (pTUS1, pTUS180, pTUS829, and pTUS206) were 8 to 64 times more resistant to the hydrophilic quinolones than the parent quinolone-susceptible strain.

Dibekacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Dibekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Dibekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Plasmid DNA isolated from this strain was introduced into Escherichia coli DH5alpha by transformation, and colonies were selected on Luria-Bertani agar plates containing 10 ug of tobramycin per ml. Analysis of restriction digests on agarose gels of DNA from a tobramycin-resistant transformant confirmed the presence of the same 50-kb plasmid that was isolated from Escherichia coli SCH92111602.

Enoxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone resistance protein NorA (NORA) [20]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Enoxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Staphylococcus aureus strain SA113; 1280
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Mechanism Description: The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus Tk2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. Escherichia coli strains containing one of the plasmids carrying the norA gene (pTUS1, pTUS180, pTUS829, and pTUS206) were 8 to 64 times more resistant to the hydrophilic quinolones than the parent quinolone-susceptible strain.

Fosfomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MURA) [21]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Fosfomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: Overexpression of the murA gene by induction of a regulated promoter can lead to greatly increased MICs, to levels that would afford clinical resistance, while having relatively low effects on fitness (relative to mutations to fosfomycin resistance found in clinical isolates).

Framycetin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Framycetin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Gentamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• 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 Co356; 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.

Gentamicin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Gentamicin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Gentamicin C

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Gentamicin C
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Hygromycin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [22]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Hygromycin B
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BE904; 562
• In Vitro Model: Escherichia coli strain CSR603; 562
• In Vitro Model: Escherichia coli strain DH1; 536056
• In Vitro Model: Escherichia coli strain JA221; 562
• In Vitro Model: Escherichia coli strain k12; 83333
• In Vitro Model: Escherichia coli strain RR1; 562
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: O-galactosidase assay
• Mechanism Description: Hygromycin B resistance is mediated by an aminocyc1ito1 phosphotransferase that inactivates by covalent addition of a phosphate to the 4-position of hygromycin B. The gene is abbreviated as aph(4).

Isepamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Isepamicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Kanamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Plasmid DNA isolated from this strain was introduced into Escherichia coli DH5alpha by transformation, and colonies were selected on Luria-Bertani agar plates containing 10 ug of tobramycin per ml. Analysis of restriction digests on agarose gels of DNA from a tobramycin-resistant transformant confirmed the presence of the same 50-kb plasmid that was isolated from Escherichia coli SCH92111602.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: The resistant strains contained an identical 6.8-kilobase plasmid, pRPG101. Transformation of pRPG101 into Escherichia coli produced high-level resistance to amikacin (greater than or equal to 256 micrograms/ml) and kanamycin (greater than or equal to 256 micrograms/ml) but unchanged susceptibilities to gentamicin, netilmicin, and tobramycin. The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [5]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Acinetobacter baumannii strain BM2580; 470
• In Vitro Model: Bacillus subtilis strain BS168; 1423
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: Resistance to aminogiycosides in Aeinetobaeter is widespread and is mainly the result of the production of enzymes which modify the antibiotics. The enzymes beiong to three ciasses: phosphotransferases (APH), acetyltransferases (AAC). A. baumahnii strain BM2580, a representative of one of these epidemics, was shown to synthesize a 3'-aminoglycoside phosphotransferase. Substrate specificity and DNA annealing studies indicated that the isozyme in A. baumannii was of a new type, designated APH(3')-VI. Cloning and localization of the kanamyein-resistance determinant Piasmids pAT235 and pAT236, constructed by inserting the 1.8kb Ace\ and 2.1 kb EcoRI fragments of plP1841, respectively, into pUC18, conferred kanamycin resistance to E. coli.

Key Molecule: kanamycin resistance protein Kmr (KMR) [23]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain JM 105; 562
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: The kanamycin resistance determinant of the broad-host-range plasmid RP4 encodes an aminoglycoside 3'-phosphotransferase of type I. The nucleotide sequence of the kanamycin resistance gene (kmr) and the right end of the insertion element IS8 of plasmid RP4 has been determined. The nucleotide sequence has been compared to five related aphA genes originating from gram-negative and gram-positive organisms and from antibiotic producers. Among these that of Tn903 shares the highest degree of similarity (60%) with the RP4 gene. Significant similarities were also detected between the amino acid sequences of the six enzymes.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [24]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Campylobacter jejuni; 197
• In Vitro Model: Escherichia coli strain JC2926 C600; 562
• Experiment for Molecule Alteration: Dideoxy method assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: A novel kanamycin phosphotransferase gene, aphA-7, was cloned from a 14-kb plasmid obtained from a strain of Campylobacter jejuni and the nucleotide sequence of the gene was determined. The presumed open reading frame of the aphA-7 structural gene was 753 bp in length and encoded a protein of 251 amino acids with a calculated weight of 29,691 Da.

Meropenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Meropenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Metronidazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: 2-Nitroimidazole nitrohydrolase (NNHA) [25]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Metronidazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: The oxygen-insensitive major and minor (nsfA and nfsB, respectively) flavoprotein nitroreductases of E. coli, were shown to reduce nitrofurans and later, metronidazole. These nitroreductases share a similar structure to the nim genes described below. Mutants of both nfsA/nfsB in E. coli show reduced susceptibility to metronidazole. A 2-nitroimidazole nitrohydrolase (NnhA) was also shown to render E. coli resistant to 2-nitroimidazoles.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G2-specific protein kinase (NIMA) [25]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Metronidazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: In B. fragilis, nimA encodes a 5-nitroimidazole reductase reducing the metronidazole analogue dimetronidazole (1,2-dimethyl-5-nitroimidazole) to the amino derivative, preventing ring fission and associated toxicity. The role of nim genes in metronidazole resistance is controversial. It has been established that overexpression of a NimA homologue from B. fragilis induces a 3-fold increase in metronidazole resistance in E. coli.

Mezlocillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Mezlocillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Nalidixic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.S80l
• Resistant Drug: Nalidixic acid
• 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) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.E84G
• Resistant Drug: Nalidixic acid
• 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) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.D476N
• Resistant Drug: Nalidixic acid
• 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) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Nalidixic acid
• 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.

Netilmicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Netilmicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Netilmicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Netilmicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Nitrofurazone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oxygen-insensitive NAD(P)H nitroreductase (NFSB) [26]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Nitrofurazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: Escherichia coli contains at least two enzymes which reduce nitrofurazone and other nitrofuran derivatives. One of these enzymes is lacking in some nitrofurazone-resistant mutant strains. We now report that there are three separable nitrofuran reductases in this organism: reductase I (mol. wt. approximately 50 000, insensitive to O2), reductase IIa (mol. wt. approximately 120 000, inhibited by oxygen), reductase IIb (mol. wt. approximately 700 000, inhibited by O2). Unstable metabolites formed during the reduction of nitrofurazone by preparations containing reductases IIa and IIb produce breaks in DNA in vitro. In vivo experiments with nitrofurazone-resistant strains, which lack reductase II but contain reductases IIa and IIb, demonstrated that lethality, mutation, and DNA breakage are all greatly increased when cultures are incubated under anaerobic conditions, i.e., conditions such that reductase II is active. These results provide further evidence for the importance of reductive activation of nitrofurazone.

Key Molecule: Nitrofurazone-reductase IIa (NFR2A) [26]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Nitrofurazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: Escherichia coli contains at least two enzymes which reduce nitrofurazone and other nitrofuran derivatives. One of these enzymes is lacking in some nitrofurazone-resistant mutant strains. We now report that there are three separable nitrofuran reductases in this organism: reductase I (mol. wt. approximately 50 000, insensitive to O2), reductase IIa (mol. wt. approximately 120 000, inhibited by oxygen), reductase IIb (mol. wt. approximately 700 000, inhibited by O2). Unstable metabolites formed during the reduction of nitrofurazone by preparations containing reductases IIa and IIb produce breaks in DNA in vitro. In vivo experiments with nitrofurazone-resistant strains, which lack reductase II but contain reductases IIa and IIb, demonstrated that lethality, mutation, and DNA breakage are all greatly increased when cultures are incubated under anaerobic conditions, i.e., conditions such that reductase II is active. These results provide further evidence for the importance of reductive activation of nitrofurazone.

Key Molecule: Nitrofurazone-reductase IIb (NFR2B) [26]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Nitrofurazone
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: THP1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0006
• Mechanism Description: Escherichia coli contains at least two enzymes which reduce nitrofurazone and other nitrofuran derivatives. One of these enzymes is lacking in some nitrofurazone-resistant mutant strains. We now report that there are three separable nitrofuran reductases in this organism: reductase I (mol. wt. approximately 50 000, insensitive to O2), reductase IIa (mol. wt. approximately 120 000, inhibited by oxygen), reductase IIb (mol. wt. approximately 700 000, inhibited by O2). Unstable metabolites formed during the reduction of nitrofurazone by preparations containing reductases IIa and IIb produce breaks in DNA in vitro. In vivo experiments with nitrofurazone-resistant strains, which lack reductase II but contain reductases IIa and IIb, demonstrated that lethality, mutation, and DNA breakage are all greatly increased when cultures are incubated under anaerobic conditions, i.e., conditions such that reductase II is active. These results provide further evidence for the importance of reductive activation of nitrofurazone.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone resistance protein NorA (NORA) [20]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Norfloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Staphylococcus aureus strain SA113; 1280
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Mechanism Description: The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus Tk2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. Escherichia coli strains containing one of the plasmids carrying the norA gene (pTUS1, pTUS180, pTUS829, and pTUS206) were 8 to 64 times more resistant to the hydrophilic quinolones than the parent quinolone-susceptible strain.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.S80l
• Resistant Drug: Ofloxacin
• 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) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.E84G
• Resistant Drug: Ofloxacin
• 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) [19]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.D476N
• Resistant Drug: Ofloxacin
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone resistance protein NorA (NORA) [20]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ofloxacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Staphylococcus aureus strain SA113; 1280
• Experiment for Molecule Alteration: Dideoxy chain-termination method assay
• Mechanism Description: The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus Tk2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. Escherichia coli strains containing one of the plasmids carrying the norA gene (pTUS1, pTUS180, pTUS829, and pTUS206) were 8 to 64 times more resistant to the hydrophilic quinolones than the parent quinolone-susceptible strain.

Piperacillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Piperacillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Ribostamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [8]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Ribostamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli strain JM103; 83333
• In Vitro Model: Bacillus circulans strain; 1397
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Streptomyces lividans strain M180; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Semi-quantitative phosphocellulose-paper binding assay method assay
• Mechanism Description: The previous demonstration that the APH gene of B. circulans could be expressed in E.coli. These contained a 5.5kb Hind3-digest insert (pCH4) or a 2.7kb Sal1-digest insert (pCH5) at the corresponding site in pBR322. Both these derivatives expressed ampicillin and ribostamycin resistance in E.coli.

Spectinomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside adenylyltransferase (AAD5) [27]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Spectinomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain 9516014-1; 562
• In Vitro Model: Escherichia coli strain k-12 J62-2; 83333
• In Vitro Model: Salmonella enterica serotype Typhimurium DT104 no. 9720921; 90371
• Experiment for Molecule Alteration: Sequencing with the QIAquick purification kit assay
• Experiment for Drug Resistance: Sensititre system assay
• Mechanism Description: The aadA genes are the only characterized genes that encode both streptomycin and spectinomycin resistance, and many of these genes are found as gene cassettes.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [28]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Spectinomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain k12; 83333
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nucleotide sequence of 1400 bp from R-plasmid R538-1 containing the streptomycin/spectinomycin adenyltransferase gene (aadA) was determined, and the location of the aadA gene was identified by a combination of insertion and deletion mutants. Its gene product, aminoglycoside 3"-adenylyltransferase (AAD(3")(9), has a Mr of 31,600.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• 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.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• 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.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

Key Molecule: Aminoglycoside adenylyltransferase (AAD5) [27]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain 9516014-1; 562
• In Vitro Model: Escherichia coli strain k-12 J62-2; 83333
• In Vitro Model: Salmonella enterica serotype Typhimurium DT104 no. 9720921; 90371
• Experiment for Molecule Alteration: Sequencing with the QIAquick purification kit assay
• Experiment for Drug Resistance: Sensititre system assay
• Mechanism Description: The aadA genes are the only characterized genes that encode both streptomycin and spectinomycin resistance, and many of these genes are found as gene cassettes.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [28]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Streptomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain k12; 83333
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nucleotide sequence of 1400 bp from R-plasmid R538-1 containing the streptomycin/spectinomycin adenyltransferase gene (aadA) was determined, and the location of the aadA gene was identified by a combination of insertion and deletion mutants. Its gene product, aminoglycoside 3"-adenylyltransferase (AAD(3")(9), has a Mr of 31,600.

Sulfathiazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [29]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.P64S
• Resistant Drug: Sulfathiazole
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain BN102; 562
• In Vitro Model: Escherichia coli strain BN122; 562
• In Vitro Model: Escherichia coli strain BN123; 562
• Experiment for Molecule Alteration: Direct PCR sequencing assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Escherichia coli BN122 and BN123 folP sequences were identical to one another, but they contained a single difference from the wild-type nucleotide sequence. The difference was a C-to-T transition at nucleotide 184, resulting in a Pro-to-Ser substitution at amino acid 64. The sequence of this region of folP aligned with DHPS sequences from a variety of additional sources. Pro64 lies very close to the active site of DHPS, adjacent to Arg63, whose side chain bonds in a hydrogen bond with an oxygen of the sulfanilamide inhibitor. Substitution of Pro64 by Ser is likely to alter the local structure of the peptide, in turn altering the ability of Arg63 to contact the inhibitor.

Tobramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Plasmid DNA isolated from this strain was introduced into Escherichia coli DH5alpha by transformation, and colonies were selected on Luria-Bertani agar plates containing 10 ug of tobramycin per ml. Analysis of restriction digests on agarose gels of DNA from a tobramycin-resistant transformant confirmed the presence of the same 50-kb plasmid that was isolated from Escherichia coli SCH92111602.

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Tobramycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Triclosan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: NADH-dependent enoyl-ACP reductase (FABL) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G93V
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• In Vitro Model: E. coli imp4231 FabI(G93V) strain; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Among the triclosan-resistant mutants, E. coli AGT11, which had a Gly93 Val mutation in fabI, FabI(G93V), showed a 95-fold higher MIC than the wild-type. On the basis of these results, Levy et al.7 carried out structural analysis and inhibition experiments on a complex of E. coli FabI with triclosan and NAD+ and found that a FabI NAD+ triclosan ternary complex was formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI. In contrast to intact FabI, overexpression of FabI(G93V) conferred greater triclosan resistance by preventing formation of the FabI NAD+ triclosan ternary complex.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Uncharacterized oxidoreductase YeiQ (YEIQ) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tartronate semialdehyde reductase (TSAR) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Glycerol dehydrogenase (GLDA) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Nitrate/nitrite transporter NarU (NARU) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Key Molecule: Outer membrane porin C (OMPC) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Key Molecule: Outer membrane porin F (OMPF) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Key Molecule: Unclear drug transporter ydjXYZ (DT-unclear) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Key Molecule: Unclear drug transporter ykgEF (DT-unclear) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Uncharacterized protein YkgG (YKGG) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: FDH-N subunit gamma (FDHNI) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Galactarate dehydratase (L-threo-forming) (GARD) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Flavohemoprotein (HCP) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Nitrate reductase 1 (narGHJI) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Key Molecule: Peptide methionine sulfoxide reductase MsrB (MSRB) [30]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Triclosan
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: A FabI NAD+ triclosan ternary complex is formed by face-to-face interaction between the phenol ring of triclosan and the nicotinamide ring of NAD+ in the active site of FabI (enoyl-acyl carrier protein reductase) and therefore highly expressed reductases (narGHJI, garR, hcp and yeaA) and dehydrogenases (fdnGHI, ykgEF, garD, gldA and yeiQ) could bind triclosan which were as the NAD(P) cofactor, thus lowering the effective triclosan concentration.

Trimethoprim

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [6]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Trimethoprim
• 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.

Key Molecule: Dihydrofolate reductase type 6 (DFRA6) [31]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Trimethoprim
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain JM101; 83333
• In Vitro Model: Escherichia coli strain k12 JM103; 83333
• In Vitro Model: Proteus mirabilis strain J120; 584
• Experiment for Molecule Alteration: Chain termination method assay
• Mechanism Description: High-level resistance to trimethoprim (Tp) (MIC > 1000 mg/L) is mediated by dihydrofolate reductases (DHFRs) which are resistant to the drug, The gene encoding the type VI DHFR was isolated from P. mirabilis strain J120 (pUk672). The hybrid plasmids were transformed into competent Escherichia coli kl2 JM103 and clones containing the DHFR gene were selected on a medium containing trimethoprim lactate (Wellcome) 100 mg/L, ampicillin 100 mg/L, isopropyl-Beta-D-galactoside and 5-bromo-4-chloro-3-indolyl-Beta-D-gal-actopyranoside (X-gal).

Viomycin sulfate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Viomycin phosphotransferase (VPH) [32]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Viomycin sulfate
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain ED8767; 562
• In Vitro Model: Streptomyces lividans strain M252; 1916
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Escherichia coli strain W5445; 562
• In Vitro Model: Streptomyces lividans strain M264; 1916
• In Vitro Model: Streptomyces lividans strain M274; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: Insertion of the BamHI fragment containing this sequence (vph) into the unique BamHI site of pBR322, in one orientation, led to expression of viomycin resistance in Escherichia coli.

Imipenem

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Metallo-beta-lactamase (VIM1) [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Imipenem
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Electroporation of Escherichia coli DH5alpha with the purified plasmid preparation yielded ampicillin-resistant transformants which contained a plasmid apparently identical to pAX22 (data not shown). DH5alpha(pAX22) produced carbapenemase activity (specific activity of crude extract, 202 +/- 14 U/mg of protein) and, compared to DH5alpha, exhibited a decreased susceptibility to several Beta-lactams.

Clinical Trial Drug(s) 1 drug(s) in total

Apramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [22]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Apramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BE904; 562
• In Vitro Model: Escherichia coli strain CSR603; 562
• In Vitro Model: Escherichia coli strain DH1; 536056
• In Vitro Model: Escherichia coli strain JA221; 562
• In Vitro Model: Escherichia coli strain k12; 83333
• In Vitro Model: Escherichia coli strain RR1; 562
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: O-galactosidase assay
• Mechanism Description: Apramycin resistance is mediated by an aminocyclitol acetyltransferase that acetylates the nitrogen at the 3 -position of apramycin.The gene is abbreviated as aac(3)Iv.

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

6'-N-Ethylnetilmicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: 6'-N-Ethylnetilmicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Enacyloxin IIA

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Outer membrane porin F (OMPF) [33]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.Q124K
• Resistant Drug: Enacyloxin IIA
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Key Molecule: Outer membrane porin F (OMPF) [33]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G316D
• Resistant Drug: Enacyloxin IIA
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Key Molecule: Outer membrane porin F (OMPF) [33]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.Q329H
• Resistant Drug: Enacyloxin IIA
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Key Molecule: Outer membrane porin F (OMPF) [33]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.A375T
• Resistant Drug: Enacyloxin IIA
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Ge2270a

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu 1 (TUFA) [34]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G257S
• Resistant Drug: Ge2270a
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Key Molecule: Elongation factor Tu 2 (TUFB) [34]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G257S
• Resistant Drug: Ge2270a
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Key Molecule: Elongation factor Tu 1 (TUFA) [34]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G275A
• Resistant Drug: Ge2270a
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Key Molecule: Elongation factor Tu 2 (TUFB) [34]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.G275A
• Resistant Drug: Ge2270a
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Kirromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu 1 (TUFA) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.G316D
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 2 (TUFB) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.G316D
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 1 (TUFA) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.A375T
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 2 (TUFB) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.A375T
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 1 (TUFA) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.A375V
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 2 (TUFB) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.A375V
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 1 (TUFA) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.Q124K
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Key Molecule: Elongation factor Tu 2 (TUFB) [35], [36], [37]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Mutantion; p.Q124K
• Resistant Drug: Kirromycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Microcin J25

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding/permease protein YojI (YOJI) [38]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Microcin J25
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli k-12; 83333
• Experiment for Molecule Alteration: Promega and one-step chromosomal gene inactivation method assay
• Experiment for Drug Resistance: Spot-on-lawn assay
• Mechanism Description: YojI, an Escherichia coli open reading frame with an unknown function, mediates resistance to the peptide antibiotic microcin J25 when it is expressed from a multicopy vector. Disruption of the single chromosomal copy of yojI increased sensitivity of cells to microcin J25. One obvious explanation for the protective effect against microcin J25 is that YojI action keeps the intracellular concentration of the peptide below a toxic level. the resistance to MccJ25 mediated by YojI involves extrusion of the peptide and that YojI is assisted by the multifunctional outer membrane protein TolC.

Pentisomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Acquired
• Resistant Drug: Pentisomicin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Pulvomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Elongation factor Tu 1 (TUFA) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.R230C
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Key Molecule: Elongation factor Tu 2 (TUFB) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.R230C
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Key Molecule: Elongation factor Tu 1 (TUFA) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.R333C
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Key Molecule: Elongation factor Tu 2 (TUFB) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.R333C
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Key Molecule: Elongation factor Tu 1 (TUFA) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.T334A
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Key Molecule: Elongation factor Tu 2 (TUFB) [39]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Missense mutation; p.T334A
• Resistant Drug: Pulvomycin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Streptothricin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Streptothricin acetyltransferase (STA) [40]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Streptothricin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces lividans strain Tk21; 1916
• In Vitro Model: Bacillus subtilis strain RM141; 1423
• In Vitro Model: Escherichia coli strain 5131-5; 562
• Experiment for Molecule Alteration: [a-32P] dCTP by the dideoxynucleoside triphosphate chain termination method assay
• Mechanism Description: The nucleotide sequence of the streptothricin acetyltransferase (STAT) gene from streptothricin-producing Streptomyces lavendulae predicts a 189-amino-acid protein of molecular weight 20,000, which is consistent with that determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme. By addition of promoter signals and a synthetic ribosome-binding (Shine-Dalgarno) sequence at an appropriate position upstream of the STAT translational start codon, the STAT gene confers streptothricin resistance on Escherichia coli and Bacillus subtilis.

References

• Ref 1: Aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im detected together in strains of both Escherichia coli and Enterococcus faecium. Antimicrob Agents Chemother. 2001 Oct;45(10):2691-4. doi: 10.1128/AAC.45.10.2691-2694.2001.
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