Molecule Information

General Information of the Molecule (ID: Mol00902)

• Name: Dihydrofolate reductase (DHFR) ,Escherichia coli
• Synonyms: DHPS; Dihydropteroate pyrophosphorylase; dhpS; b3177; JW3144
• Molecule Type: Protein
• Gene Name: folP
• Gene ID: 66672921
• Sequence:
  MKLFAQGTSLDLSHPHVMGILNVTPDSFSDGGTHNSLIDAVKHANLMINAGATIIDVGGE
  STRPGAAEVSVEEELQRVIPVVEAIAQRFEVWISVDTSKPEVIRESAKVGAHIINDIRSL
  SEPGALEAAAETGLPVCLMHMQGNPKTMQEAPKYDDVFAEVNRYFIEQIARCEQAGIAKE
  KLLLDPGFGFGKNLSHNYSLLARLAEFHHFNLPLLVGMSRKSMIGQLLNVGPSERLSGSL
  ACAVIAAMQGAHIIRVHDVKETVEAMRVVEATLSAKENKRYE
• Function: Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.
• Uniprot ID: DHPS_ECOLI

Kingdom: N.A.
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Enterobacterales
Family: Enterobacteriaceae
Genus: Escherichia
Species: Escherichia coli

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Clofazimine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Clofazimine
• Molecule Alteration: Missense mutation; p.T53A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Clofazimine
• Molecule Alteration: Missense mutation; p.P55R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Dapsone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Dapsone
• Molecule Alteration: Missense mutation; p.T53A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Dapsone
• Molecule Alteration: Missense mutation; p.P55R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.T53A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Ofloxacin
• Molecule Alteration: Missense mutation; p.P55R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Missense mutation; p.T53A
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Rifampin
• Molecule Alteration: Missense mutation; p.P55R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

Sulfathiazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Escherichia coli infection [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Sulfathiazole
• Molecule Alteration: Missense mutation; p.P64S
• 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.

Investigative Drug(s) 1 drug(s) in total

Dapsone/Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Leprosy [1]

• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Resistant Drug: Dapsone/Rifampin
• Molecule Alteration: Missense mutation; p.P55R
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium leprae isolates; 1769
• In Vivo Model: Footpad granuloma from M. leprae-infected nude mice model; Mus musculus
• Experiment for Molecule Alteration: PCR and single-stranded conformational polymorphism (SSCP) assay
• Experiment for Drug Resistance: Mouse footpad assay
• Mechanism Description: The mutations genes reported in this study have been demonstrated to be responsible for drug resistance by mouse footpad assay.

References

• Ref 1: Mutations in genes related to drug resistance in Mycobacterium leprae isolates from leprosy patients in Korea. J Infect. 2005 Jan;50(1):6-11. doi: 10.1016/j.jinf.2004.03.012.
• Ref 2: Characterization of mutations contributing to sulfathiazole resistance in Escherichia coli. Antimicrob Agents Chemother. 1998 Jan;42(1):88-93. doi: 10.1128/AAC.42.1.88.