Molecule Information

General Information of the Molecule (ID: Mol00942)

• Name: DNA-directed RNA polymerase subunit beta' (RPOC) ,Clostridioides difficile
• Synonyms: RNAP subunit beta'; RNA polymerase subunit beta'; Transcriptase subunit beta'; CD630_00670
• Molecule Type: Protein
• Gene Name: rpoC
• Gene ID: 66352565
• Sequence:
  MFELNNFESIKIALASPEKIRQWSRGEVKKPETINYRTLKPEKDGLFCERIFGPQKDWEC
  HCGKYRRVRYKGVVCDRCGVEVTKSKVRRERMGHIELAAPMSHIWYFKGIPSRMGLLLDM
  SPRSLEKILYFASYVVVDPGETGLNEKQLLTEKEYRTALEKYGYTFTVGMGAEAVKTLLQ
  NIDLEQQSKDLRAELKDSTGQKKVRTIRRLEVVEAFKKSGNKPEWMILDAIPVIPPDLRP
  MVQLDGGRFATSDLNDLYRRVINRNNRLKRLLELGAPDIIVRNEKRMLQEAVDALIDNGR
  RGRPVTGPGNRPLKSLSDMLKGKQGRFRQNLLGKRVDYSGRSVIVVGPELKFYQCGLPKK
  MALELFKPFVMDKLVKEGYAHNIKSAKSIVEKVKPEVWDVLEDVIKSHPVLLNRAPTLHR
  LGIQAFEPILVEGKAIKLHPLVCTAYNADFDGDQMAVHVPLSVEAQAEARFLMLSVNNIL
  APKDGSPITTPSQDMVLGCYYLTIEAQDGAKGTGMVFKDFNELLLAYYNKSVHLHALVKL
  KVTLEDGRSSLVESTVGRFIFNENIPQDLGFVDRKENPFALEVDFLADKKSLGKIIDKCF
  RKHGNTETAELLDYIKALGFKYSTLGGITVAVDDMSVPEEKKVFIAEAEAKVDKYEKAYR
  RGLISDEERYEKVIETWTETTDKVTDALMGGLDRLNNIYIMAHSGARGSKNQIRQLAGMR
  GLMANASGKTVEIPVKSNFREGLSVLEYFTSSHGARKGLADTAIRTAESGYLTRRLVDVS
  QDVIVREIDCGTEDTTEIYAIKEGNEVIEEIYDRIVGRYTIDPILNPETGEVIVEADSMI
  QEDEAETIVALGIEKIRIRTVLNCKTNHGVCSKCYGRNLATGKEVNIGEAVGIIAAQSIG
  EPGTQLTMRTFHTGGVAGADITQGLPRVEELFEARKPKGLAVITEVSGRVEIDETGKRKE
  VNVIPEEGETQTYVIPYGSRLKVKQGQMLEAGDPLTQGFINPHDIVRVNGVKGVQEYIVK
  EVQRVYRLQGVDVNDKHIEVIVRQMLSKVKVEDPGDTDLLPGGYEDVLTFNECNKDAIDK
  GLRPAVAKRVLLGITKASLATDSFLSAASFQETTRVLTEAAIKGKEDHLIGLKENVILGK
  LIPAGTGMKKYRNIAVEKIED
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
• Uniprot ID: RPOC_CLOD6

Kingdom: N.A.
Phylum: Firmicutes
Class: Clostridia
Order: Eubacteriales
Family: Peptostreptococcaceae
Genus: Clostridioides
Species: Clostridioides difficile

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Fidaxomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Bacterial infection [1]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Fidaxomicin
• Molecule Alteration: Missense mutation; p.D244Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridioides difficile ATCC 43255; 499175
• In Vitro Model: Clostridioides difficile NB95009; 1496
• In Vitro Model: Clostridioides difficile NB95026; 1496
• In Vitro Model: Clostridioides difficile NB95031; 1496
• In Vitro Model: Clostridioides difficile NB95047; 1496
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: NB95026-JAL0865 had a single mutation encoding a D244Y substitution in the RNA polymerase subunit Beta.Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase and cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms.

Disease Class: Clostridium difficile infection [2]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Resistant Drug: Fidaxomicin
• Molecule Alteration: Missense mutation; p.D273Y
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Despite both drugs share a common target, the nucleotide substitution within rpoB of fidaxomicin and RIF-resistant strains locate differently. In vitro study has revealed that amino acid substitutions in either rpoB at E1073K, Q1074K and V1143F or rpoC at D273Y confer resistance to fidaxomicin.

Vancomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Bacterial infection [1]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Resistant Drug: Vancomycin
• Molecule Alteration: Missense mutation; p.D244Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Clostridioides difficile ATCC 43255; 499175
• In Vitro Model: Clostridioides difficile NB95009; 1496
• In Vitro Model: Clostridioides difficile NB95026; 1496
• In Vitro Model: Clostridioides difficile NB95031; 1496
• In Vitro Model: Clostridioides difficile NB95047; 1496
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: NB95026-JAL0865 had a single mutation encoding a D244Y substitution in the RNA polymerase subunit Beta.Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase and cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms.

References

• Ref 1: In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. J Antimicrob Chemother. 2014 Jan;69(1):41-4. doi: 10.1093/jac/dkt302. Epub 2013 Jul 25.
• Ref 2: Insights into drug resistance mechanisms in Clostridium difficile .Essays Biochem. 2017 Mar 3;61(1):81-88. doi: 10.1042/EBC20160062. Print 2017 Feb 28. 10.1042/EBC20160062