Drug Information

Drug (ID: DG00001) and It's Reported Resistant Information

• Name: Triclosan
• Synonyms: Triclosan; 3380-34-5; 5-CHLORO-2-(2,4-DICHLOROPHENOXY)PHENOL; 2,4,4'-Trichloro-2'-hydroxydiphenyl ether; Irgasan; Cloxifenolum; Triclosanum; Irgasan DP300; Stri-Dex Face Wash; Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-; Lexol 300; Stri-Dex Cleansing Bar; 5-Chloro-2-(2,4-dichloro-phenoxy)-phenol; Triclosanum [INN-Latin]; CH 3565; DP-300; Caswell No 186A; C12H7Cl3O2; UNII-4NM5039Y5X; HSDB 7194; CHEBI:164200; Ether, 2'-hydroxy-2,4,4'-trichlorodiphenyl; Phenyl ether, 2'-hydroxy-2,4,4'-trichloro-; EINECS 222-182-2; CHEMBL849; EPA; Aquasept; Cliniclean; Cloxifenol; Manusept; Sapoderm; TCL; Trisan; Clearasil DailyFace Wash; Dermtek Brand of Triclosan; GlaxoSmithKline Brand of Triclosan; Microshield T; Oxy Skin Wash; Pharmachem Brand of Triclosan; Reckitt Brand of Triclosan; SSL Brand of Triclosan; Ster Zac Bath Concentrate; SterZac Bath Concentrate; Trans Canaderm Brand of Triclosan; Triclosan Pharmachem Brand; Triclosan Reckitt Brand; IN1424; Irgasan DP 300; CH-3565; Johnson & Johnson Brand of Triclosan; Procter & Gamble Brand of Triclosan; Ster-Zac Bath Concentrate; Stri-Dex cleansing bar (TN); Triclosan (USP/INN); Triclosan [USAN:BAN:INN]; 2,4,4'-Trichloro-2'-hydroxy diphenyl ether; 2-Hydroxy-2',4,4'-trichlorodiphenyl Ether; WL-1001
• Indication:
  In total 2 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1]
  Trypanosomiasis [ICD-11: 1D51-1F53]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Pneumonia [ICD-11: CA40]; [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [1]
• Target: Plasmodium Enoyl-ACP reductase (Malaria fabI); Q965D5_PLAFA; [1]
• Formula: C12H7Cl3O2
• IsoSMILES: C1=CC(=C(C=C1Cl)O)OC2=C(C=C(C=C2)Cl)Cl
• InChI: 1S/C12H7Cl3O2/c13-7-1-3-11(9(15)5-7)17-12-4-2-8(14)6-10(12)16/h1-6,16H
• InChIKey: XEFQLINVKFYRCS-UHFFFAOYSA-N
• PubChem CID: 5564
• ChEBI ID: CHEBI:164200
• TTD Drug ID: D00CSQ
• DrugBank ID: DB08604

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

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: NADH-dependent enoyl-ACP reductase (FABL) [1]

• Molecule Alteration: Missense mutation; p.G93V
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• 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) [1]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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: MATE family efflux transporter (ABEM) [2]

• 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.

References

• Ref 1: Signature gene expression profile of triclosan-resistant Escherichia coli. J Antimicrob Chemother. 2010 Jun;65(6):1171-7. doi: 10.1093/jac/dkq114. Epub 2010 Apr 21.
• Ref 2: 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.