Disease Information

General Information of the Disease (ID: DIS00147)

• Name: Clostridioides difficile intestinal infection
• ICD: ICD-11: 1A04

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

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

Chloramphenicol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Chloramphenicol acetyltransferase (CAT) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Chloramphenicol
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The inactivation of drug undergoes by the addition of side chain that generates a steric hindrance effect, which in turn disrupts the target-binding affinity. Two copies of catD gene encoding for CHL acetyltransferase locate at the mobile regions Tn4453a and Tn4453b of C. difficile. CHL acetyltransferase catalyses the relocation of acetyl group from acetyl-CoA to CHL, resulting in 3-O-acetyl CHL, which cannot bind to a ribosome and loses its antimicrobial action.

Ciprofloxacin XR

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Mutation; p.T82I
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Mutations in the gyrA or gyrB gene within quinolone resistance-determining region lead to the reduction in fidelity or prevention of drug binding via the target conformation change. Although several amino acid substitutions have been noted in GyrA and/or GyrB, the most frequent amino acid change has been recognized at T82I in GyrA subunit.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug export protein MepA (cdeA) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Ciprofloxacin XR
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In C. difficile, two secondary active transporters belonging to the MFS and MATE families have been reported to be associated with drug resistance. Heterologous expression of the clostridial Cme protein in the MFS subfamily promotes ERY resistance in Enterococcus faecalis. A sodium-dependent efflux pump of the MATE subfamily encoded by the cdeA gene of C. difficile attributes resistance to norfloxacin and ciprofloxacin when the gene was overexpressed in Escherichia coli.

Clindamycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase (ErmB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Clindamycin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The cellular methylation in C. difficile has been proposed to induce resistance to macrolides (erythromycin, ERY), lincosamide (clindamycin) and streptogramin B antibiotic family. These drugs target at a bacterial 50S ribosomal subunit, causing the inhibition of peptide chain growth by blocking the movement of ribosome. ERY ribosomal methylase B (ErmB) is responsible for ribosomal methylation at the specific site of 23S rRNA, resulting in the prevention of antibiotic binding.

Erythromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase (ErmB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The cellular methylation in C. difficile has been proposed to induce resistance to macrolides (erythromycin, ERY), lincosamide (clindamycin) and streptogramin B antibiotic family. These drugs target at a bacterial 50S ribosomal subunit, causing the inhibition of peptide chain growth by blocking the movement of ribosome. ERY ribosomal methylase B (ErmB) is responsible for ribosomal methylation at the specific site of 23S rRNA, resulting in the prevention of antibiotic binding.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Major facilitator superfamily (MFS) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Erythromycin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In C. difficile, two secondary active transporters belonging to the MFS and MATE families have been reported to be associated with drug resistance. Heterologous expression of the clostridial Cme protein in the MFS subfamily promotes ERY resistance in Enterococcus faecalis. A sodium-dependent efflux pump of the MATE subfamily encoded by the cdeA gene of C. difficile attributes resistance to norfloxacin and ciprofloxacin when the gene was overexpressed in Escherichia coli.

Fidaxomicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Mutation; p.E1073K+p.Q1074K+p.V1143F
• Resistant Drug: Fidaxomicin
• 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.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA-directed RNA polymerase subunit beta' (RPOC) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Missense mutation; p.D273Y
• Resistant Drug: Fidaxomicin
• 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.

Metronidazole

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Thioredoxin (TRX) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Metronidazole
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The decrement of redox proteins including pyruvate:ferredoxin oxidoreductase (OR), pyruvate:flavodoxin OR, thioredoxin and thioredoxin reductase are thought to be responsible for MTZ resistance as they are required for drug activation.

Key Molecule: Thioredoxin (TRX) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Metronidazole
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The decrement of redox proteins including pyruvate:ferredoxin oxidoreductase (OR), pyruvate:flavodoxin OR, thioredoxin and thioredoxin reductase are thought to be responsible for MTZ resistance as they are required for drug activation.

Norfloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug export protein MepA (cdeA) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Norfloxacin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In C. difficile, two secondary active transporters belonging to the MFS and MATE families have been reported to be associated with drug resistance. Heterologous expression of the clostridial Cme protein in the MFS subfamily promotes ERY resistance in Enterococcus faecalis. A sodium-dependent efflux pump of the MATE subfamily encoded by the cdeA gene of C. difficile attributes resistance to norfloxacin and ciprofloxacin when the gene was overexpressed in Escherichia coli.

Ofloxacin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Mutation; p.T82I
• Resistant Drug: Ofloxacin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Mutations in the gyrA or gyrB gene within quinolone resistance-determining region lead to the reduction in fidelity or prevention of drug binding via the target conformation change. Although several amino acid substitutions have been noted in GyrA and/or GyrB, the most frequent amino acid change has been recognized at T82I in GyrA subunit.

Rifampin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Mutation; p.R505K
• Resistant Drug: Rifampin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: RIFs (rifampicin and rifaximin) have recently been used as another option for CDI treatment. Nevertheless, the resistance to RIFs in C. difficile has been reported. These drugs target on a DNA-dependent RNA polymerase (RNAP), resulting in the extension of short transcript blockage. Point mutations within the rpoB gene encoding for beta-subunit of RNAP cause resistance to RIFs. Among identified amino acid substitutions, the R505K substitution has been mostly evident to promote the high level of resistance.

Rifaximin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-directed RNA polymerase subunit beta (RPOB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Mutation; p.R505K
• Resistant Drug: Rifaximin
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: RIFs (rifampicin and rifaximin) have recently been used as another option for CDI treatment. Nevertheless, the resistance to RIFs in C. difficile has been reported. These drugs target on a DNA-dependent RNA polymerase (RNAP), resulting in the extension of short transcript blockage. Point mutations within the rpoB gene encoding for beta-subunit of RNAP cause resistance to RIFs. Among identified amino acid substitutions, the R505K substitution has been mostly evident to promote the high level of resistance.

Tetracycline

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tetracycline resistance protein TetM (TETM) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Of the resistance mechanisms, C. difficile produces ribosomal protection protein that impedes the attachment of the drug to a ribosome. The TetM protein that functions as ribosomal protectant has been identified in TET-resistant C. difficile strains, whereas the presence of other Tet proteins such as Tet(W) and Tet(44) has also been recognized. The TetM exhibits homology to EF-G and shares the same binding region in a ribosome. The binding of the TetM protein to a ribosome accompanying with the GTP hydrolysis allows conformational change of the ribosome, resulting in the dissociation of TET from its binding site. Cellular protein synthesis is then recovered through the binding of EF-G after the release of hydrolysed TetM.

Key Molecule: Tetracycline resistance protein TetW (TETW) [1]

• Resistant Disease: Human immunodeficiency virus infection [ICD-11: 1C62.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Of the resistance mechanisms, C. difficile produces ribosomal protection protein that impedes the attachment of the drug to a ribosome. The TetM protein that functions as ribosomal protectant has been identified in TET-resistant C. difficile strains, whereas the presence of other Tet proteins such as Tet(W) and Tet(44) has also been recognized. The TetM exhibits homology to EF-G and shares the same binding region in a ribosome. The binding of the TetM protein to a ribosome accompanying with the GTP hydrolysis allows conformational change of the ribosome, resulting in the dissociation of TET from its binding site. Cellular protein synthesis is then recovered through the binding of EF-G after the release of hydrolysed TetM.

Key Molecule: Ribosomal tetracycline resistance protein tet (TET(44)) [1]

• Resistant Disease: Human immunodeficiency virus infection [ICD-11: 1C62.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Tetracycline
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Of the resistance mechanisms, C. difficile produces ribosomal protection protein that impedes the attachment of the drug to a ribosome. The TetM protein that functions as ribosomal protectant has been identified in TET-resistant C. difficile strains, whereas the presence of other Tet proteins such as Tet(W) and Tet(44) has also been recognized. The TetM exhibits homology to EF-G and shares the same binding region in a ribosome. The binding of the TetM protein to a ribosome accompanying with the GTP hydrolysis allows conformational change of the ribosome, resulting in the dissociation of TET from its binding site. Cellular protein synthesis is then recovered through the binding of EF-G after the release of hydrolysed TetM.

Clinical Trial Drug(s) 1 drug(s) in total

Pristinamycin IA

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase (ErmB) [1]

• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Molecule Alteration: Expression; Inherence
• Resistant Drug: Pristinamycin IA
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The cellular methylation in C. difficile has been proposed to induce resistance to macrolides (erythromycin, ERY), lincosamide (clindamycin) and streptogramin B antibiotic family. These drugs target at a bacterial 50S ribosomal subunit, causing the inhibition of peptide chain growth by blocking the movement of ribosome. ERY ribosomal methylase B (ErmB) is responsible for ribosomal methylation at the specific site of 23S rRNA, resulting in the prevention of antibiotic binding.

References

• Ref 1: 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