Drug Information

Drug (ID: DG00127) and It's Reported Resistant Information

• Name: Telithromycin
• Synonyms: Ketek; Levviax; TEL; HMR 3647; HMR3647; RU 66647; RU66647; HMR-3647; Ketek (TN); RU-66647; Telithromycin [USAN:BAN:INN]; Telithromycin (JAN/USAN/INN); (1R,2R,4R,6R,7R,8R,10R,13R,14S)-7-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-13-ethyl-6-methoxy-2,4,6,8,10,14-hexamethyl-17-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-12,15-dioxa-17-azabicyclo[12.3.0]heptadecane-3,9,11,16-tetrone; (1R,2R,4R,6R,7R,8R,10S,13R,14S)-7-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-13-ethyl-6-methoxy-2,4,6,8,10,14-hexamethyl-17-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-12,15-dioxa-17-azabicyclo[12.3.0]heptadecane-3,9,11,16-tetrone; (1R,2R,4R,6S,7R,8R,10R,13R,14S)-7-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-13-ethyl-6-methoxy-2,4,6,8,10,14-hexamethyl-17-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-12,15-dioxa-17-azabicyclo[12.3.0]heptadecane-3,9,11,16-tetrone; (1R,2S,4R,6R,7R,8R,10R,13R,14S)-7-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-13-ethyl-6-methoxy-2,4,6,8,10,14-hexamethyl-17-[4-(4-pyridin-3-ylimidazol-1-yl)butyl]-12,15-dioxa-17-azabicyclo[12.3.0]heptadecane-3,9,11,16-tetrone; 11,12-Dideoxy-3-des(2,6-dideoxy-3-C,3-O-dimethyl-alpha-L-altropyranosyloxy)-6-O-methyl-3-oxo-12,11-(oxycarbonylimino)-N11-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]erythromycin 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 (3 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2], [3]
  Streptococcal pharyngitis [ICD-11: 1B51]; [6]
  Surgical wound infection [ICD-11: NE81]; [7]
• Target: Bacterial 50S ribosomal RNA (Bact 50S rRNA); NOUNIPROTAC; [1]
• Formula: C43H65N5O10
• IsoSMILES: CC[C@@H]1[C@@]2([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H](C(=O)[C@H](C(=O)O1)C)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)N(C(=O)O2)CCCCN4C=C(N=C4)C5=CN=CC=C5)C
• InChI: 1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33-,36-,37-,38-,40+,42-,43-/m1/s1
• InChIKey: LJVAJPDWBABPEJ-PNUFFHFMSA-N
• PubChem CID: 3002190
• ChEBI ID: CHEBI:29688
• TTD Drug ID: D09HNR
• VARIDT ID: DR00576
• INTEDE ID: DR1544
• DrugBank ID: DB00976

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.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Macrolide 2'-phosphotransferase II (MPHB) [8], [9], [10]

• 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 AG100A; 562
• In Vitro Model: Escherichia coli DB10; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Mph enzymes inactivate macrolides by phosphorylating the 2'-OH of the essential dimethylamino sugar, preventing it from binding the ribosome, and providing the chemical rationale for the resistance phenotype.

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) [6]

• 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-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) [7]

• 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) [7]

• 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: 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 7: 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.
• Ref 8: Purification and characterization of macrolide 2'-phosphotransferase type II from a strain of Escherichia coli highly resistant to macrolide antibiotics. FEMS Microbiol Lett. 1992 Oct 1;76(1-2):89-94. doi: 10.1016/0378-1097(92)90369-y.
• Ref 9: Resistance phenotypes conferred by macrolide phosphotransferases. FEMS Microbiol Lett. 2007 Apr;269(2):317-22. doi: 10.1111/j.1574-6968.2007.00643.x. Epub 2007 Feb 16.
• Ref 10: The evolution of substrate discrimination in macrolide antibiotic resistance enzymes. Nat Commun. 2018 Jan 9;9(1):112. doi: 10.1038/s41467-017-02680-0.