Drug Information

Drug (ID: DG00242) and It's Reported Resistant Information

• Name: Macrolides
• Synonyms: Tylosin; tylosin tartrate; Tilosina; Tylosinum; UNII-YEF4JXN031; Tylosine; Tylocine; Tylan; Tylosin A; 1401-69-0; YEF4JXN031; Fradizine; CHEBI:17658; Vubityl 200; Tylosinum [INN-Latin]; Tylosine [INN-French]; Tilosina [INN-Spanish]; HSDB 7022; EINECS 215-754-8; AI3-29799; SR-05000002057; Tylosin [USP:INN:BAN]; Tylan (TN); Tylosin (USP/INN); AC1NQX0W
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2], [3]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2], [3]
  Bacterial meningitis [ICD-11: 1D02]; [4]
  Campylobacteriosis [ICD-11: 1C40]; [5]
  Staphylococcus meningitis [ICD-11: 1B54]; [6]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (3 diseases)
  Actinomycetoma [ICD-11: 1C43]; [7]
  Bacillus infection [ICD-11: 1C4Y]; [8]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [9]
• Target: Bacterial 23S ribosomal RNA (Bact 23S rRNA); NOUNIPROTAC; [1]
• Formula: C46H77NO17
• IsoSMILES: CC[C@@H]1[C@H](/C=C(/C=C/C(=O)[C@@H](C[C@@H]([C@@H]([C@H]([C@@H](CC(=O)O1)O)C)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)C)O[C@H]3C[C@@]([C@H]([C@@H](O3)C)O)(C)O)N(C)C)O)CC=O)C)\\C)CO[C@H]4[C@@H]([C@@H]([C@@H]([C@H](O4)C)O)OC)OC
• InChI: 1S/C46H77NO17/c1-13-33-30(22-58-45-42(57-12)41(56-11)37(52)26(5)60-45)18-23(2)14-15-31(49)24(3)19-29(16-17-48)39(25(4)32(50)20-34(51)62-33)64-44-38(53)36(47(9)10)40(27(6)61-44)63-35-21-46(8,55)43(54)28(7)59-35/h14-15,17-18,24-30,32-33,35-45,50,52-55H,13,16,19-22H2,1-12H3/b15-14+,23-18+/t24-,25+,26-,27-,28+,29+,30-,32-,33-,35+,36-,37-,38-,39-,40-,41-,42-,43+,44+,45-,46-/m1/s1
• InChIKey: WBPYTXDJUQJLPQ-VMXQISHHSA-N
• PubChem CID: 5280440
• ChEBI ID: CHEBI:17658
• TTD Drug ID: D0Q6OS
• DrugBank ID: DB11475

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  IDUE: Irregularity in Drug Uptake and Drug Efflux

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 ermC' (ERMC) [10], [11], [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus subtilis strain BD170; 1423
• In Vitro Model: Bacillus subtilis strain BD430; 1423
• In Vitro Model: Bacillus subtilis strain BD431; 1423
• In Vitro Model: Bacillus subtilis strain BD488; 1423
• In Vitro Model: Bacillus subtilis strain BD81; 1423
• Experiment for Molecule Alteration: SDS-PAGE assay
• Mechanism Description: The ermC gene of plasmid pE194 specifies resistance to the macrolidelincosamide-streptogramin B antibiotics. pE194 specifies an RNA methylase that can utilize either 50 S ribosomes or 23 S rRNA as substrates,with a specific dimethylation of adenine in 23 S rRNA.

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Oleandomycin glycosyltransferase oleD (OLED) [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 GT-28; 562
• In Vitro Model: Escherichia coli MurG; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: OleD displays broad acceptor specificity and hence will inactivate a wider range of macrolide antibiotics including tylosin and erythromycin.

Staphylococcus meningitis [ICD-11: 1B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Erythromycin resistance protein (ERM33) [6]

• Molecule Alteration: Expression; Gene recombination
• Resistant Disease: Staphylococcus sciuri infection [ICD-11: 1B54.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus sciuri plasmid pSCFS1; 1296
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Staphylococcus sciuri Gene erm(33), Encoding Inducible Resistance to Macrolides, Lincosamides, and Streptogramin B Antibiotics, Is a Product of Recombination between erm(C) and erm(A).

Actinomycetoma [ICD-11: 1C43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [13]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Tylosin resistance ATP-binding protein TlrC (TLRC) [7]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces fradiae strain; 1906
• In Vitro Model: Treptomyces fradia strain; 1906
• Experiment for Molecule Alteration: Northern blotting analysis
• Mechanism Description: A tylosin(Ty)-producing strain of Streptomyces fradiae contains at least three genes, tlrA, tlrB, tlrC, specifying resistance to Ty (TyR).

Key Molecule: Tylosin resistance ATP-binding protein TlrC (TLRC) [7]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Streptomyces fradiae infection [ICD-11: 1C43.5]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptomyces fradiae strain; 1906
• In Vitro Model: Treptomyces fradia strain; 1906
• Experiment for Molecule Alteration: Northern blotting analysis
• Mechanism Description: The product of the tlrA gene is an rRNA methylase responsible for dimethylation of a specific A residue in S. fradiae 23s rRNA (Zalacain and Cundliffe, 1989). In contrast, the Ty-inducible resistance encoded by tlrB or tlrC appears to be specific for Ty and each imparts lower levels of TyR than does tlrA.

Bacillus infection [ICD-11: 1C4Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase ermG (ERMG) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacillus sphaericus infection [ICD-11: 1C4Y.4]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Bacillus subtilis strain BD1107; 1423
• In Vitro Model: Bacillus subtilis strain BD1117; 1423
• In Vitro Model: Bacillus subtilis strain BD1146; 1423
• In Vitro Model: Bacillus subtilis strain BD1156; 1423
• In Vitro Model: Bacillus subtilis strain BD1158; 1423
• In Vitro Model: Bacillus subtilis strain BD624; 1423
• In Vitro Model: Bacillus subtilis strain BD629; 1423
• In Vitro Model: Bacillus subtilis strain BD630; 1423
• In Vitro Model: Bacillus subtilis strain CU403; 1423
• Experiment for Molecule Alteration: Southern blotting assay
• Mechanism Description: One of the mechanisms of bacterial resistance to aminoglycosides is the production of aminoglycoside N-acetyl-transferase (AAC) enzymes which acetylate the amino groups present in the molecule of the aminoglycoside, preventing their interaction with the ribosome. ermG specifies a 29,000-dalton protein, the synthesis of which is induced by erythromycin. S1 nuclease mapping was used to identify the transcriptional start site. These experiments demonstrated the presence on the ermG mRNA of a 197 to 198-base leader.

Bacterial meningitis [ICD-11: 1D02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: MsrC (MSRC) [4]

• Molecule Alteration: Truncated mutantion; Disruption (nt 1251 to 1879)
• Sensitive Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Enterococcus faecium TX2465; 1352
• In Vitro Model: Escherichia coli TX1330; 668369
• In Vitro Model: Escherichia coli TX2046; 668369
• In Vitro Model: Escherichia coli TX2597; 668369
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci.

References

• Ref 1: Glycosylation of macrolide antibiotics. Purification and kinetic studies of a macrolide glycosyltransferase from Streptomyces antibioticus. J Biol Chem. 2000 Apr 21;275(16):11713-20. doi: 10.1074/jbc.275.16.11713.
• Ref 2: The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5336-41. doi: 10.1073/pnas.0607897104. Epub 2007 Mar 21.
• Ref 3: Characterization of a Streptomyces antibioticus gene cluster encoding a glycosyltransferase involved in oleandomycin inactivation. Gene. 1993 Nov 30;134(1):139-40. doi: 10.1016/0378-1119(93)90189-a.
• Ref 4: Disruption of an Enterococcus faecium species-specific gene, a homologue of acquired macrolide resistance genes of staphylococci, is associated with an increase in macrolide susceptibility. Antimicrob Agents Chemother. 2001 Jan;45(1):263-6. doi: 10.1128/AAC.45.1.263-266.2001.
• Ref 5: [Overview of resistance mechanisms in Campylobacter]Zhonghua Yu Fang Yi Xue Za Zhi. 2018 Oct 6;52(10):1072-1077. doi: 10.3760/cma.j.issn.0253-9624.2018.10.021.
• Ref 6: Staphylococcus sciuri gene erm(33), encoding inducible resistance to macrolides, lincosamides, and streptogramin B antibiotics, is a product of recombination between erm(C) and erm(A). Antimicrob Agents Chemother. 2002 Nov;46(11):3621-3. doi: 10.1128/AAC.46.11.3621-3623.2002.
• Ref 7: Homology between proteins controlling Streptomyces fradiae tylosin resistance and ATP-binding transport. Gene. 1991 Jun 15;102(1):27-32. doi: 10.1016/0378-1119(91)90533-h.
• Ref 8: Cloning and analysis of ermG, a new macrolide-lincosamide-streptogramin B resistance element from Bacillus sphaericus. J Bacteriol. 1987 Jan;169(1):340-50. doi: 10.1128/jb.169.1.340-350.1987.
• Ref 9: Cloning vectors, mutagenesis, and gene disruption (ermR) for the erythromycin-producing bacterium Aeromicrobium erythreum. Appl Environ Microbiol. 1991 Sep;57(9):2758-61. doi: 10.1128/aem.57.9.2758-2761.1991.
• Ref 10: Molecular mechanism of drug-dependent ribosome stalling. Mol Cell. 2008 Apr 25;30(2):190-202. doi: 10.1016/j.molcel.2008.02.026.
• Ref 11: The ermC leader peptide: amino acid alterations leading to differential efficiency of induction by macrolide-lincosamide-streptogramin B antibiotics. J Bacteriol. 1990 Jul;172(7):3772-9. doi: 10.1128/jb.172.7.3772-3779.1990.
• Ref 12: Mono- and dimethylating activities and kinetic studies of the ermC 23 S rRNA methyltransferase. J Biol Chem. 1989 Feb 15;264(5):2615-24.
• Ref 13: Characterization of a glycosyl transferase inactivating macrolides, encoded by gimA from Streptomyces ambofaciens. Antimicrob Agents Chemother. 1998 Oct;42(10):2612-9. doi: 10.1128/AAC.42.10.2612.