Disease Information

General Information of the Disease (ID: DIS00005)

• Name: Gram-negative bacterial infection
• ICD: ICD-11: 1B74-1G40

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 15 drug(s) in total

Amoxicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [1], [2]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Amoxicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Acinetobacter johnsonii LIM75; 40214
• In Vitro Model: Aeromonas allosaccharophila LIM82; 656
• In Vitro Model: Citrobacter freundii LIM86; 546
• In Vitro Model: Escherichia coli MFDpir; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: All known class 3 integrons harbour gene cassettes encoding resistance to Beta-lactams (blaIMP, blaGES, blaBEL, blaOXA-256) and aminoglycosides [aac(6')-Ib].

Ceftazidime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Beta-lactamase (BLA) [1], [2]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ceftazidime
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Acinetobacter johnsonii LIM75; 40214
• In Vitro Model: Aeromonas allosaccharophila LIM82; 656
• In Vitro Model: Citrobacter freundii LIM86; 546
• In Vitro Model: Escherichia coli MFDpir; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; broth microdilution method assay
• Mechanism Description: All known class 3 integrons harbour gene cassettes encoding resistance to Beta-lactams (blaIMP, blaGES, blaBEL, blaOXA-256) and aminoglycosides [aac(6')-Ib].

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Ribosomal RNA large subunit methyltransferase N (CFRC) [3]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Clostridioides difficile T10; 1215084
• In Vitro Model: Clostridium bolteae 90B3; 997895
• In Vitro Model: Escherichia coli TG1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: The cfr gene encodes a 23S rRNA methyltransferase, which causes C-8 modification in A2503 located in the peptidyl transferase region of bacterial ribosome.This mechanism confers PhLOPSA (phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A) resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [4]

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

Chlortetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [4]

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

Colistin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Colistin resistance protein (MCR-3.3-Unclear) [5]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Mutation; .
• Resistant Drug: Colistin A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Aeromonas veronii 172; 654
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: This strain showed resistance to both Beta-lactams and phenicols and had borderline susceptibility to colistin, which was mediated by mcr-3.3 alone.

Colistin B

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Colistin resistance protein (MCR-3.3-Unclear) [5]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Mutation; .
• Resistant Drug: Colistin B
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Aeromonas veronii 172; 654
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: This strain showed resistance to both Beta-lactams and phenicols and had borderline susceptibility to colistin, which was mediated by mcr-3.3 alone.

Dibekacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [6]

• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dibekacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

Florfenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Ribosomal RNA large subunit methyltransferase N (CFRC) [3]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Florfenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Clostridioides difficile T10; 1215084
• In Vitro Model: Clostridium bolteae 90B3; 997895
• In Vitro Model: Escherichia coli TG1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: The cfr gene encodes a 23S rRNA methyltransferase, which causes C-8 modification in A2503 located in the peptidyl transferase region of bacterial ribosome.This mechanism confers PhLOPSA (phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A) resistance.

Gentamicin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [6]

• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gentamicin A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

Kanamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [6]

• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Kanamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [4]

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

Nalidixic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [4]

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

Sisomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [6]

• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sisomicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

Streptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MipA/OmpV family protein (MIPA) [4]

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

Tedizolid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [7]

• Resistant Disease: Gram-negative bacterial infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Missense mutation; p.A1345G
• Resistant Drug: Tedizolid
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Gram-positive bacteria MRSA strain N315; .
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Mechanism Description: Tedizolid resistance is uncommon and tedizolid's capacity to select for cross-resistance to other antimicrobials is incompletely understood. To the best of our knowledge, this is the first time that an rpoB mutation has been implicated in resistance to PhLOPSa antimicrobials.

Tobramycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [6]

• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tobramycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

References

• Ref 1: Characterisation of class 3 integrons with oxacillinase gene cassettes in hospital sewage and sludge samples from France and Luxembourg. Int J Antimicrob Agents. 2016 Oct;48(4):431-4. doi: 10.1016/j.ijantimicag.2016.06.018. Epub 2016 Jul 28.
• Ref 2: Improved purification and characterization of the OXA-2 beta-lactamase. Biochem J. 1984 Dec 15;224(3):1009-13. doi: 10.1042/bj2241009.
• Ref 3: A cfr-like gene cfr(C) conferring linezolid resistance is common in Clostridium difficile. Int J Antimicrob Agents. 2017 Sep;50(3):496-500. doi: 10.1016/j.ijantimicag.2017.03.013. Epub 2017 Jun 27.
• Ref 4: Outer membrane proteomics of kanamycin-resistant Escherichia coli identified MipA as a novel antibiotic resistance-related protein. FEMS Microbiol Lett. 2015 Jun;362(11):fnv074. doi: 10.1093/femsle/fnv074. Epub 2015 May 3.
• Ref 5: Chromosome-Mediated mcr-3 Variants in Aeromonas veronii from Chicken Meat. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01272-17. doi: 10.1128/AAC.01272-17. Print 2017 Nov.
• Ref 6: Novel aminoglycoside 2''-phosphotransferase identified in a gram-negative pathogen. Antimicrob Agents Chemother. 2013 Jan;57(1):452-7. doi: 10.1128/AAC.02049-12. Epub 2012 Nov 5.
• Ref 7: Identification of a novel tedizolid resistance mutation in rpoB of MRSA after in vitro serial passage .J Antimicrob Chemother. 2021 Jan 19;76(2):292-296. doi: 10.1093/jac/dkaa422. 10.1093/jac/dkaa422