Drug Information

Drug (ID: DG00145) and It's Reported Resistant Information

• Name: Apramycin
• Synonyms: AC1O533Z; XZNUGFQTQHRASN-PHTOHMOASA-N
• Indication:
  In total 1 Indication(s)
  Gram-negative bacterial infection [ICD-11: 1B74-1G40]; Phase 1; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3], [4]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [5]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2]
• Target: Bacterial 16S ribosomal RNA (Bact 16S rRNA); NOUNIPROTAC; [1]
• Formula: C21H41N5O11
• IsoSMILES: CN[C@H]1[C@H]([C@@H]2[C@H](C[C@H]([C@H](O2)O[C@@H]3[C@H](C[C@H]([C@@H]([C@H]3O)O)N)N)N)O[C@@H]1O[C@@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)N)O)O)O
• InChI: 1S/C21H41N5O11/c1-26-11-14(30)18-8(33-20(11)37-21-16(32)13(29)10(25)9(4-27)34-21)3-7(24)19(36-18)35-17-6(23)2-5(22)12(28)15(17)31/h5-21,26-32H,2-4,22-25H2,1H3/t5-,6+,7-,8+,9-,10-,11+,12+,13+,14-,15-,16-,17-,18+,19+,20-,21-/m1/s1
• InChIKey: XZNUGFQTQHRASN-XQENGBIVSA-N
• PubChem CID: 3081545
• ChEBI ID: CHEBI:2790
• TTD Drug ID: D0B0FU
• DrugBank ID: DB04626

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 methyltransferase PikR1 (PIKR1) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: rRNA methyltransferase PikR2 (PIKR2) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli BL21(DE3)pLysS; 866768
• In Vitro Model: Escherichia coli S17-1; 1227813
• In Vitro Model: Streptomyces antibioticus ATCC 11891; 1890
• In Vitro Model: Streptomyces venezuelae ATCC 15439; 54571
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Modification of 23S rRNA, which is the target site for methymycin and its derivatives, by PikR1 and PikR2 is a primary self-resistance mechanism.

Key Molecule: 16S rRNA (adenine(1408)-N(1))-methyltransferase (KAMB) [3], [4]

• 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 BL21(DE3); 469008
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The 16S ribosomal RNA methyltransferase enzymes that modify nucleosides in the drug binding site to provide self-resistance in aminoglycoside-producing micro-organisms have been proposed to comprise two distinct groups of S-adenosyl-l-methionine (SAM)-dependent RNA enzymes, namely the kgm and kam families.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminocyclitol acetyltransferase ApmA (APMA) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• In Vitro Model: Escherichia coli JM101; 562
• In Vitro Model: Staphylococcus aureus ST398; 523796
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The apmA gene coded for a protein of 274 amino acids that was related only distantly to acetyltransferases involved in chloramphenicol or streptogramin A resistance.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (A3AC) [5]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain BE904; 562
• In Vitro Model: Escherichia coli strain CSR603; 562
• In Vitro Model: Escherichia coli strain DH1; 536056
• In Vitro Model: Escherichia coli strain JA221; 562
• In Vitro Model: Escherichia coli strain k12; 83333
• In Vitro Model: Escherichia coli strain RR1; 562
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: O-galactosidase assay
• Mechanism Description: Apramycin resistance is mediated by an aminocyclitol acetyltransferase that acetylates the nitrogen at the 3 -position of apramycin.The gene is abbreviated as aac(3)Iv.

References

• Ref 1: Beta-glucosylation as a part of self-resistance mechanism in methymycin/pikromycin producing strain Streptomyces venezuelae. Biochemistry. 2003 Dec 23;42(50):14794-804. doi: 10.1021/bi035501m.
• Ref 2: A gene cluster for macrolide antibiotic biosynthesis in Streptomyces venezuelae: architecture of metabolic diversity. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12111-6. doi: 10.1073/pnas.95.21.12111.
• Ref 3: Determination of the target nucleosides for members of two families of 16S rRNA methyltransferases that confer resistance to partially overlapping groups of aminoglycoside antibiotics. Nucleic Acids Res. 2009 Sep;37(16):5420-31. doi: 10.1093/nar/gkp575. Epub 2009 Jul 9.
• Ref 4: Expansion of the aminoglycoside-resistance 16S rRNA (m(1)A1408) methyltransferase family: expression and functional characterization of four hypothetical enzymes of diverse bacterial origin. Biochim Biophys Acta. 2014 Sep;1844(9):1648-55. doi: 10.1016/j.bbapap.2014.06.012. Epub 2014 Jun 22.
• Ref 5: Analysis of a bacterial hygromycin B resistance gene by transcriptional and translational fusions and by DNA sequencing. Nucleic Acids Res. 1983 Oct 11;11(19):6895-911. doi: 10.1093/nar/11.19.6895.
• Ref 6: Novel apramycin resistance gene apmA in bovine and porcine methicillin-resistant Staphylococcus aureus ST398 isolates. Antimicrob Agents Chemother. 2011 Jan;55(1):373-5. doi: 10.1128/AAC.01124-10. Epub 2010 Sep 27.