Drug Information

Drug (ID: DG00313) and It's Reported Resistant Information

• Name: Clarithromycin
• Synonyms: Abbotic; Adel; Astromen; Biaxin; Bicrolid; CTY; Clacine; Clambiotic; Claribid; Claricide; Clarith; Clarithromycina; Clarithromycine; Clarithromycinum; Claritromicina; Clathromycin; Cyllid; Cyllind; Helas; Heliclar; Klacid; Klaciped; Klaricid; Klarid; Klarin; Klax; Kofron; Mabicrol; Macladin; Maclar; Mavid; Naxy;Veclam; Zeclar; Biaxin HP; Biaxin XL; Biaxin filmtab; Biaxin xl filmtab; Clarithromycin extended release; Clarithromycin suspension or tablets; Klaricid Pediatric; Klaricid XL; TE031; A-56268; ANX-015; Abbott-56268; Biaxin (TN); Clacid (TN); Claridar (TN); Claripen (TN); Clarithromycine [INN-French]; Clarithromycinum [INN-Latin]; Claritromicina [INN-Spanish]; Crixan (TN); DRG-0099; Fromilid (TN);Infex (TN); Klabax (TN); Klaricid (TN); Klaricid H.P; Lactoferrin B & Clarithromycin; Lactoferrin H & Clarithromycin; SDP-015; TE-031; Vikrol (TN); CLM & IL-12; CRL-1605 & Clarithromycin; Clarithromycin & Interleukin-12; Klaricid H.P.; O(6)-methylerythromycin; Clarithromycin (JP15/USP/INN); Clarithromycin [USAN:INN:BAN:JAN]; Hydro-2H-pyran-2-yl]oxy}-7-methoxy-3,5,7,9,11,13-hexame; (14R)-14-Hydroxyclarithromycin; 6-O-Methylerythromycin; 6-O-Methylerythromycin a
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2], [3], [4], [5]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [6]
  Helicobacter pylori infection [ICD-11: DA60]; [7]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [8]
  Pneumonia [ICD-11: CA40]; [9]
  Streptococcal pharyngitis [ICD-11: 1B51]; [10]
  Surgical wound infection [ICD-11: NE81]; [11]
• Target: Bacterial 50S ribosomal RNA (Bact 50S rRNA); NOUNIPROTAC; [1]
• Formula: C38H69NO13
• IsoSMILES: CC[C@@H]1[C@@]([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)O)(C)O
• InChI: 1S/C38H69NO13/c1-15-26-38(10,45)31(42)21(4)28(40)19(2)17-37(9,47-14)33(52-35-29(41)25(39(11)12)16-20(3)48-35)22(5)30(23(6)34(44)50-26)51-27-18-36(8,46-13)32(43)24(7)49-27/h19-27,29-33,35,41-43,45H,15-18H2,1-14H3/t19-,20-,21+,22+,23-,24+,25+,26-,27+,29-,30+,31-,32+,33-,35+,36-,37-,38-/m1/s1
• InChIKey: AGOYDEPGAOXOCK-KCBOHYOISA-N
• PubChem CID: 84029
• ChEBI ID: CHEBI:3732
• TTD Drug ID: D0Z1ZM
• VARIDT ID: DR00713
• INTEDE ID: DR0336
• DrugBank ID: DB01211

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermE (ERME) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AS19; 562
• In Vitro Model: Escherichia coli AS19-RrmA-; 562
• In Vitro Model: Escherichia coli DH10B; 316385
• In Vitro Model: Escherichia coli JC7623; 562
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics.ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs.

Key Molecule: erm(X)cj (Unclear) [6]

• Molecule Alteration: Frameshift mutation; Codon 216 frame shift
• Resistant Disease: Corynebacterium jeikeium infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Corynebacterium diphtheriae isolate; 1717
• In Vitro Model: Corynebacterium glutamicum kO8; 1718
• In Vitro Model: Corynebacterium jeikeium isolates; 38289
• In Vitro Model: Escherichia coli ATCC 25923; 562
• In Vitro Model: Escherichia coli strain XL1-Blue MRF9; 562
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion methods assay; agar dilution methods assay
• Mechanism Description: Abundant amplificationproducts of slightly less than 400 bp were generated from DNAisolated from the 17 MLSb-resistant strains, whereas no am-plification products were generated with the DNA isolatedfrom the three susceptible strains. The DNA sequences of the amplification products showed 95% identity to the erm(X) gene isolated from a C. xerosis strain,erm(X)cx or ermCX. Thus, MLSb resistance in C. jeikeiumis associated with the presence of an allele, erm(X)cj, of the class Xermgenes. The first 215 amino acids of the predicted polypeptides for strains CJ12 and CJ21 are 93.5 and 98.6% identical to Erm(X)cx, the Erm protein from C. xerosi. The major difference between the two Erm(X)cj polypeptides and the Erm(X)cx polypeptide is a frame shift within codon 216. This results in the Erm(X)cj polypeptides being 31 amino acids longer than Erm(X)cx.

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm (ERM39) [8]

• Molecule Alteration: Missense mutation; Putative initiation codon GTG>CTG
• Resistant Disease: Mycobacterium fortuitum infection [ICD-11: 1B2Z.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium peregrinum ATCC14467; 43304
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Mueller-Hinton (MH) broth assay
• Mechanism Description: The erm genes are a diverse collection of methylases that add one or two methyl groups to the adenine at position 2058 (Escherichia coli numbering) of the 23S rRNA; this modification impairs the binding of macrolides to ribosomes, and thus reduces the inhibitory activity of these agents.

Streptococcal pharyngitis [ICD-11: 1B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMA) [10]

• Molecule Alteration: Methylation; Macrolide-binding site on the ribosome
• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Macrolide resistance commonly occurs due to methylation of the macrolide-binding site on the ribosome by methyltransferases encoded by the erm group of genes, Induction of erm(A) occurs by translational attenuationInduction of erm(A) occurs by translational attenuation.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Erythromycin esterase (EREA2) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Community-acquired pneumonia [ICD-11: CA40.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Disk diffusion test assay; E-strip test assay
• Mechanism Description: One mechanism of macrolide resistance is via drug inactivation: enzymatic hydrolysis of the macrolactone ring catalyzed by erythromycin esterases, EreA and EreB.

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

Surgical wound infection [ICD-11: NE81]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Erythromycin resistance protein (ERM38) [11]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Mycobacterium smegmatis infection [ICD-11: 1B2Z.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium smegmatis mc2155; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pMIP12; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pOMV20; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pOMV30; 246196
• Experiment for Molecule Alteration: MALDI mass spectrometry assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Erm (38) is a specific dimethyltransferase. The strain obtained drug resistance by adding two methyl groups to A2058 in Mycobacterium 23SrRNA.

Key Molecule: Erythromycin resistance protein (ERM38) [11]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Mycobacterium smegmatis infection [ICD-11: 1B2Z.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium smegmatis mc2155; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pMIP12; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pOMV20; 246196
• In Vitro Model: Mycobacterium smegmatis mc2155/pOMV30; 246196
• Experiment for Molecule Alteration: MALDI mass spectrometry assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Erm (38) is a specific dimethyltransferase. The strain obtained drug resistance by adding two methyl groups to A2058 in Mycobacterium 23SrRNA.

References

• Ref 1: Activity of the ketolide telithromycin is refractory to Erm monomethylation of bacterial rRNA. Antimicrob Agents Chemother. 2002 Jun;46(6):1629-33. doi: 10.1128/AAC.46.6.1629-1633.2002.
• Ref 2: Expression of the macrolide-lincosamide-streptogramin-B-resistance methylase gene, ermE, from Streptomyces erythraeus in Escherichia coli results in N6-monomethylation and N6,N6-dimethylation of ribosomal RNA. Gene. 1987;55(2-3):319-25. doi: 10.1016/0378-1119(87)90291-5.
• Ref 3: Domain V of 23S rRNA contains all the structural elements necessary for recognition by the ErmE methyltransferase. J Bacteriol. 1994 Nov;176(22):6999-7004. doi: 10.1128/jb.176.22.6999-7004.1994.
• Ref 4: ErmE methyltransferase recognition elements in RNA substrates. J Mol Biol. 1998 Sep 18;282(2):255-64. doi: 10.1006/jmbi.1998.2024.
• Ref 5: ErmE methyltransferase recognizes features of the primary and secondary structure in a motif within domain V of 23 S rRNA. J Mol Biol. 1999 Feb 19;286(2):365-74. doi: 10.1006/jmbi.1998.2504.
• Ref 6: Inducible macrolide resistance in Corynebacterium jeikeium. Antimicrob Agents Chemother. 2001 Jul;45(7):1982-9. doi: 10.1128/AAC.45.7.1982-1989.2001.
• Ref 7: Helicobacter pylori infection and antibiotic resistance - from biology to clinical implicationsNat Rev Gastroenterol Hepatol. 2021 Sep;18(9):613-629. doi: 10.1038/s41575-021-00449-x. Epub 2021 May 17.
• Ref 8: Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum. J Antimicrob Chemother. 2005 Feb;55(2):170-7. doi: 10.1093/jac/dkh523. Epub 2004 Dec 8.
• Ref 9: Mechanism and diversity of the erythromycin esterase family of enzymes. Biochemistry. 2012 Feb 28;51(8):1740-51. doi: 10.1021/bi201790u. Epub 2012 Feb 10.
• Ref 10: Unusual resistance patterns in macrolide-resistant Streptococcus pyogenes harbouring erm(A). J Antimicrob Chemother. 2009 Jan;63(1):42-6. doi: 10.1093/jac/dkn432. Epub 2008 Oct 24.
• Ref 11: Mycobacterium smegmatis Erm(38) is a reluctant dimethyltransferase. Antimicrob Agents Chemother. 2005 Sep;49(9):3803-9. doi: 10.1128/AAC.49.9.3803-3809.2005.