Disease Information

General Information of the Disease (ID: DIS00134)

• Name: Urinary tract infection
• ICD: ICD-11: GC08

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 11 drug(s) in total

Amikacin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Sensitive Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Sensitive Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Sensitive Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Sensitive Drug: Amikacin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Ampicillin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ampicillin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Clindamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC protein lsaC (lsaC-Unclear) [2]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Clindamycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Streptococcus agalactiae UCN70; 1311
• In Vitro Model: Streptococcus agalactiae isolates; 1311
• In Vitro Model: Streptococcus agalactiae BM132; 1319
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 ug/ml), clindamycin (0.03 to 2 ug/ml), dalfopristin (2 to >32 ug/ml), and tiamulin (0.12 to 32 ug/ml), whereas no change in MICs of erythromycin (0.06 ug/ml), azithromycin (0.03 ug/ml), spiramycin (0.25 ug/ml), telithromycin (0.03 ug/ml), and quinupristin (8 ug/ml) was observed. The phenotype was renamed the LS(A)P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins.

Co-trimoxazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Co-trimoxazole
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Colistin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Transcriptional regulatory protein (PHOP) [3]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Missense mutation; p.D191Y
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Klebsiella pneumoniae kp75; 573
• In Vitro Model: Klebsiella pneumoniae ATCC 53153; 573
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The mutated protein PhoP activates the transcription of the pmrHFIJkLM operon, the product of which leads to synthesis of L-amino-arabinose and ultimately to colistin resistance in k. pneumoniae.These modifications create a more positively charged lipopolysaccharide and thus reduce the affinity of LPS to positively charged polymyxins.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.90del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.H159D
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1844; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; c.700C>T
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1845; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.G68D
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1846; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.391_421del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Missense mutation; p.Q72K
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii AL1848; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.76_78del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Key Molecule: Multifunctional fusion protein (LPXA) [4], [5]

• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Molecule Alteration: Frameshift mutation; c.364_809del
• Resistant Drug: Colistin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter baumannii ATCC 19606; 575584
• In Vitro Model: Acinetobacter baumannii FADDI008; 470
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: A critical first step in the action of polymyxins is the electrostatic interaction between the positively charged peptide and the negatively charged lipid A, the endotoxic component of lipopolysaccharide (LPS).A. baumannii type strain ATCC 19606, colistin-resistant variants contain mutations within genes essential for lipid A biosynthesis (either lpxA, lpxC, or lpxD) and that these strains have lost the ability to produce lipid A and therefore LPS.

Dalfopristin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC protein lsaC (lsaC-Unclear) [2]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dalfopristin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Streptococcus agalactiae UCN70; 1311
• In Vitro Model: Streptococcus agalactiae isolates; 1311
• In Vitro Model: Streptococcus agalactiae BM132; 1319
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 ug/ml), clindamycin (0.03 to 2 ug/ml), dalfopristin (2 to >32 ug/ml), and tiamulin (0.12 to 32 ug/ml), whereas no change in MICs of erythromycin (0.06 ug/ml), azithromycin (0.03 ug/ml), spiramycin (0.25 ug/ml), telithromycin (0.03 ug/ml), and quinupristin (8 ug/ml) was observed. The phenotype was renamed the LS(A)P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins.

Gentamicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Gentamicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli serogroup O11; 1095705
• In Vitro Model: Escherichia coli serogroup O17; 1010800
• In Vitro Model: Escherichia coli serogroup O73; 2170725
• In Vitro Model: Escherichia coli serogroup O77; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Microdilution method assay
• Mechanism Description: All the UTI outbreak CgA strains in this study contained the same class 1 integron dfrA17-aadA5 gene cassette arrangement with 100% sequence match, suggesting clonal spread of the bacterial strain itself. While aminoglycoside adenyltransferase A (aadA ) and dihydrofolate reductase A (dfrA ), encoding resistance to streptomycin and trimethoprim.

Lincomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC protein lsaC (lsaC-Unclear) [2]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Lincomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Streptococcus agalactiae UCN70; 1311
• In Vitro Model: Streptococcus agalactiae isolates; 1311
• In Vitro Model: Streptococcus agalactiae BM132; 1319
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 ug/ml), clindamycin (0.03 to 2 ug/ml), dalfopristin (2 to >32 ug/ml), and tiamulin (0.12 to 32 ug/ml), whereas no change in MICs of erythromycin (0.06 ug/ml), azithromycin (0.03 ug/ml), spiramycin (0.25 ug/ml), telithromycin (0.03 ug/ml), and quinupristin (8 ug/ml) was observed. The phenotype was renamed the LS(A)P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins.

Tiamulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC protein lsaC (lsaC-Unclear) [2]

• Resistant Disease: Klebsiella pneumoniae [ICD-11: CA40.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tiamulin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Streptococcus agalactiae UCN70; 1311
• In Vitro Model: Streptococcus agalactiae isolates; 1311
• In Vitro Model: Streptococcus agalactiae BM132; 1319
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 ug/ml), clindamycin (0.03 to 2 ug/ml), dalfopristin (2 to >32 ug/ml), and tiamulin (0.12 to 32 ug/ml), whereas no change in MICs of erythromycin (0.06 ug/ml), azithromycin (0.03 ug/ml), spiramycin (0.25 ug/ml), telithromycin (0.03 ug/ml), and quinupristin (8 ug/ml) was observed. The phenotype was renamed the LS(A)P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins.

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: Urinary tract infection [ICD-11: GC08.1]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Trimethoprim
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli 1387; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Mechanism Description: The most common resistant mechanism involves expressing trimethoprim insensitive variants of DHFR within mobile genetic elements, such as plasmids, transposons and integrons.

References

• Ref 1: Global spread of mobile antimicrobial drug resistance determinants in human and animal Escherichia coli and Salmonella strains causing community-acquired infections. Clin Infect Dis. 2009 Aug 1;49(3):365-71. doi: 10.1086/600301.
• Ref 2: Cross-resistance to lincosamides, streptogramins A, and pleuromutilins due to the lsa(C) gene in Streptococcus agalactiae UCN70. Antimicrob Agents Chemother. 2011 Apr;55(4):1470-4. doi: 10.1128/AAC.01068-10. Epub 2011 Jan 18.
• Ref 3: Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. Antimicrob Agents Chemother. 2015 May;59(5):2780-4. doi: 10.1128/AAC.05055-14. Epub 2015 Mar 2.
• Ref 4: Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother. 2010 Dec;54(12):4971-7. doi: 10.1128/AAC.00834-10. Epub 2010 Sep 20.
• Ref 5: Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii. Antimicrob Agents Chemother. 2014;58(1):518-26. doi: 10.1128/AAC.01597-13. Epub 2013 Nov 4.
• Ref 6: dfrA27, a new integron-associated trimethoprim resistance gene from Escherichia coli. J Antimicrob Chemother. 2009 Feb;63(2):405-6. doi: 10.1093/jac/dkn474. Epub 2008 Nov 13.