Drug Information

Drug (ID: DG00142) and It's Reported Resistant Information

• Name: Trimethoprim
• Synonyms: Abaprim; Alprim; Anitrim; Antrima; Antrimox; Bacdan; Bacidal; Bacide; Bacin; Bacta; Bacterial; Bacticel; Bactin; Bactoprim; Bactramin; Bencole; Bethaprim; Biosulten; Briscotrim; Chemotrin; Cidal; Colizole; Conprim; Cotrimel; Deprim; Duocide; Esbesul; Espectrin; Euctrim; Exbesul; Fermagex; Fortrim; Futin; Idotrim; Ikaprim; Instalac; Kombinax; Lagatrim; Lastrim; Methoprim; Metoprim; Monoprim; Monotrim; Monotrimin; Novotrimel; Omstat; Oraprim; Pancidim; Polytrim; Priloprim; Primosept; Primsol; Proloprim; Protrin; Purbal; Resprim; Roubac; Roubal; Salvatrim; Setprin; Sinotrim; Stopan; Streptoplus; Sugaprim; Sulfamar; Sulfamethoprim; Sulfoxaprim; Sulmeprim; Sulthrim; Sultrex; Syraprim; Tiempe; Toprim; Trimanyl; Trimethioprim; Trimethoprime; Trimethoprimum; Trimethopriom; Trimetoprim; Trimetoprima; Trimexazole; Trimexol; Trimezol; Trimogal; Trimono; Trimopan; Trimpex; Triprim; Trisul; Trisulcom; Trisulfam; Trisural; Uretrim; Urobactrim; Utetrin; Velaten; Wellcoprim; Wellcoprin; Xeroprim; Zamboprim; Bacterial [Antibiotic]; Colizole DS; Component of Bactrim; Component of Septra; Lagatrim Forte; ResprimForte; Septrin DS; Septrin Forte; Septrin S; Trimetoprim [DCIT]; Trimetoprim [Polish]; BW 5672; KUC103659N; NIH 204; T 7883; Trimpex 200; WR 5949; Alcorim-F; Apo-Sulfatrim; BW 56-72; Co-Trimoxizole; Monotrim (TN); NIH 204 (VAN); Proloprim (TN); Smz-Tmp; Sulfamethoxazole & Trimethoprim; TCMDC-125538; Tmp-Ratiopharm; Trimeth/Sulfa; Trimethopim(TMP); Trimethoprim & VRC3375; Trimethoprime [INN-French]; Trimethoprimum [INN-Latin]; Trimetoprima [INN-Spanish]; Trimez-IFSA; Trimpex (TN); Triprim (TN); U-Prin; Uro-D S; BW-56-72; KSC-4-158; AZT + TMP/SMX (mixture) combination; Trimethoprim (JAN/USP/INN); Trimethoprim [USAN:BAN:INN:JAN]
• Indication:
  In total 1 Indication(s)
  Urinary tract infection [ICD-11: GC08]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (11 diseases)
  Bacteremia [ICD-11: MA15]; [1]
  Cholera [ICD-11: 1A00]; [2]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
  Infective endocarditis [ICD-11: BB40]; [1]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [1]
  Pneumonia [ICD-11: CA40]; [4]
  Salmonellosis [ICD-11: 1A09]; [5]
  Serious necrotizing pneumonia [ICD-11: CA43]; [1]
  Surgical wound infection [ICD-11: NE81]; [1]
  Toxic shock syndrome [ICD-11: 1C45]; [1]
  Urinary tract infection [ICD-11: GC08]; [6]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [7]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [7]
• Target: Dihydrofolate reductase (DHFR); DYR_HUMAN; [1]
• Formula: C14H18N4O3
• IsoSMILES: COC1=CC(=CC(=C1OC)OC)CC2=CN=C(N=C2N)N
• InChI: 1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)
• InChIKey: IEDVJHCEMCRBQM-UHFFFAOYSA-N
• PubChem CID: 5578
• ChEBI ID: CHEBI:45924
• TTD Drug ID: D0AO5H
• VARIDT ID: DR00590
• INTEDE ID: DR1648
• DrugBank ID: DB00440

Type(s) of Resistant Mechanism of This Drug

  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 Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Cholera [ICD-11: 1A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [8]

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

Key Molecule: Dihydrofolate reductase (DHFR) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• In Vitro Model: Vibrio cholerae PL96; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA15 lead to drug resistance.

Key Molecule: Dihydrofolate reductase (DHFR) [2]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli k-12 strain TOP10; 83333
• In Vitro Model: Vibrio cholerae O1 C10488; 127906
• In Vitro Model: Vibrio cholerae O1 strain CO943; 127906
• In Vitro Model: Vibrio cholerae O139 1811/98; 45888
• In Vitro Model: Vibrio cholerae O139 2055; 45888
• In Vitro Model: Vibrio cholerae O139 AS207; 45888
• In Vitro Model: Vibrio cholerae O139 E712; 45888
• In Vitro Model: Vibrio cholerae O139 HkO139-SXTS; 45888
• In Vitro Model: Vibrio cholerae O139 strain MO10; 345072
• Experiment for Molecule Alteration: Sequencing assay
• Mechanism Description: Many recent Asian clinical Vibrio cholerae E1 Tor O1 and O139 isolates are resistant to the antibiotics sulfamethoxazole (Su), trimethoprim (Tm), chloramphenicol (Cm), and streptomycin (Sm). The corresponding resistance genes are located on large conjugative elements (SXT constins) that are integrated into prfC on the V. cholerae chromosome. The DNA sequences of the antibiotic resistance genes in the SXT constin in MO10, an O139 isolate. In SXT(MO10), these genes are clustered within a composite transposon-like structure found near the element's 5' end. The genes conferring resistance to Cm (floR), Su (sulII), and Sm (strA and strB) correspond to previously described genes, whereas the gene conferring resistance to Tm, designated dfr18, is novel.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PG153/1; 666
• In Vitro Model: Vibrio cholerae PG170; 666
• In Vitro Model: Vibrio cholerae PL96; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of dfrA5, ereA2 lead to drug resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae PL107b; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aac(6')-Ib lead to drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio cholerae infection [ICD-11: 1A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio cholerae O39 strain AS634; 666
• Experiment for Molecule Alteration: PCR and DNA sequencing assay
• Experiment for Drug Resistance: Commercial antimicrobial discs assay
• Mechanism Description: The expression of aadA1-S lead to drug resistance.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase type 6 (DFRA6) [7]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Proteus mirabilis infection [ICD-11: 1A00-1C4Z]
• 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).

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [3]

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

Key Molecule: Dihydrofolate reductase type 6 (DFRA6) [7]

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

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Catalase isozyme A/Tetracycline efflux MFS transporter/Dihydropteroate synthase (CATA1/TETB/SUL) [5]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella agona 231; 58095
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Disc diffusion assay
• Mechanism Description: The multiresistance plasmid from S. Agona strain 231 carried the chloramphenicol resistance gene catA1 coding for a type A chloramphenicol acetyltransferase and the resistance gene tet(B) coding for a tetracycline/minocycline exporter. This plasmid also harboured the streptomycin resistance gene strA coding for an aminoglycoside phosphotransferase and the sulphonamide resistance gene sul1 which represents part of the 3' conserved segment of class 1 integrons.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Superficial skin infection by Staphylococcus aureus infection [ICD-11: 1B21.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

Toxic shock syndrome [ICD-11: 1C45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-11: Circulatory system diseases

Infective endocarditis [ICD-11: BB40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

Key Molecule: MATE family efflux transporter (ABEM) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AbeM was found to be an H+-coupled multidrug efflux pump and a unique member of the MATE family which lead to drug resistance.

Serious necrotizing pneumonia [ICD-11: CA43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-16: Genitourinary system diseases

Urinary tract infection [ICD-11: GC08]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Dihydrofolate reductase (DHFR) [6]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Urinary tract infection [ICD-11: GC08.1]
• 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.

ICD-21: Symptoms/clinical signs/unclassified clinical findings

Bacteremia [ICD-11: MA15]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

ICD-22: Injury/poisoning/certain external causes consequences

Surgical wound infection [ICD-11: NE81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Lincomycin resistance efflux pump (LMRS) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• In Vitro Model: Staphylococcus aureus OM505; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: LmrS is a multidrug efflux pump of the major facilitator superfamily from staphylococcus aureus.

References

• Ref 1: LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Antimicrob Agents Chemother. 2010 Dec;54(12):5406-12. doi: 10.1128/AAC.00580-10. Epub 2010 Sep 20.
• Ref 2: Molecular analysis of antibiotic resistance gene clusters in vibrio cholerae O139 and O1 SXT constins. Antimicrob Agents Chemother. 2001 Nov;45(11):2991-3000. doi: 10.1128/AAC.45.11.2991-3000.2001.
• Ref 3: Mechanisms of resistance in multiple-antibiotic-resistant Escherichia coli strains of human, animal, and food origins. Antimicrob Agents Chemother. 2004 Oct;48(10):3996-4001. doi: 10.1128/AAC.48.10.3996-4001.2004.
• Ref 4: AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob Agents Chemother. 2005 Oct;49(10):4362-4. doi: 10.1128/AAC.49.10.4362-4364.2005.
• Ref 5: Class 1 integron-associated gene cassettes in Salmonella enterica subsp. enterica serovar Agona isolated from pig carcasses in Brazil. J Antimicrob Chemother. 2005 May;55(5):776-9. doi: 10.1093/jac/dki081. Epub 2005 Mar 10.
• 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.
• Ref 7: Nucleotide sequence of dihydrofolate reductase type VI. J Med Microbiol. 1991 Oct;35(4):214-8. doi: 10.1099/00222615-35-4-214.
• Ref 8: Occurrence of antibiotic resistance gene cassettes aac(6')-Ib, dfrA5, dfrA12, and ereA2 in class I integrons in non-O1, non-O139 Vibrio cholerae strains in India. Antimicrob Agents Chemother. 2002 Sep;46(9):2948-55. doi: 10.1128/AAC.46.9.2948-2955.2002.
• Ref 9: Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrob Agents Chemother. 2009 Dec;53(12):5312-6. doi: 10.1128/AAC.00748-09. Epub 2009 Sep 21.