Drug Information

Drug (ID: DG00173) and It's Reported Resistant Information

• Name: Plazomicin
• Synonyms: ACHN-490; UNII-LYO9XZ250J; 1154757-24-0; LYO9XZ250J; Plazomicin [USAN:INN]; Plazomicin (USAN); ZINC68150640; DB12615; D10151; D-Streptamine,
• Indication:
  In total 4 Indication(s)
  Bronchitis [ICD-11: CA20]; Approved; [1], [2]
  Prostate disease [ICD-11: GA91]; Approved; [1], [2]
  Urinary tract infection [ICD-11: GC08]; Approved; [1], [2]
  Pancreatic cancer [ICD-11: 2C10]; Phase 3; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2]
  Bacterial meningitis [ICD-11: 1D02]; [3]
• Target: Mitochondrial rRNA methyltransferase 2 (MRM2); MRM2_HUMAN; [1]
• Formula: C25H48N6O10
• IsoSMILES: C[C@@]1(CO[C@@H]([C@@H]([C@H]1NC)O)O[C@H]2[C@@H](C[C@@H]([C@H]([C@@H]2O)O[C@@H]3[C@@H](CC=C(O3)CNCCO)N)N)NC(=O)[C@H](CCN)O)O
• InChI: 1S/C25H48N6O10/c1-25(37)11-38-24(18(35)21(25)29-2)41-20-15(31-22(36)16(33)5-6-26)9-14(28)19(17(20)34)40-23-13(27)4-3-12(39-23)10-30-7-8-32/h3,13-21,23-24,29-30,32-35,37H,4-11,26-28H2,1-2H3,(H,31,36)/t13-,14+,15-,16+,17+,18-,19-,20+,21-,23-,24-,25+/m1/s1
• InChIKey: IYDYFVUFSPQPPV-PEXOCOHZSA-N
• PubChem CID: 42613186
• TTD Drug ID: D0E6BB
• INTEDE ID: DR2136
• DrugBank ID: DB12615

Type(s) of Resistant Mechanism of This Drug

  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

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1], [2]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Staphylococcus aureus isolates; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: AAC(6')-APH(2") is an enzyme with 6'-N-acetyltransferase and 2"-O-phosphotransferase activities.The bifunctional AAC(6')-APH(2") has the capacity to inactivate virtually all clinically important aminoglycosides through N- and O-acetylation and phosphorylation of hydroxyl groups.

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase type IA [AAC(2')-IA] [4]

• Sensitive Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Acetyltransferase assay
• Experiment for Drug Resistance: Time-Kill assay; Cytotoxicity assay
• Mechanism Description: Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6' position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2'-N-acetyltransferase type Ia [AAC(2')-Ia], which reduces the antibiotic's potency. Silver acetate is a potent inhibitor of AAC(2')-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2')-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.

Bacterial meningitis [ICD-11: 1D02]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside phosphotransferase (APH) [3]

• Resistant Disease: Enterococcus faecium meningitis [ICD-11: 1D01.2]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecium SF11770; 1352
• In Vitro Model: Escherichia coli kHE5-2a; 562
• In Vitro Model: Escherichia coli strain DH10b(pMW119); 316385
• Experiment for Molecule Alteration: PCR
• Mechanism Description: High-level gentamicin resistance (MIC >= 500 ug/ml) in enterococci is predominantly mediated by aac(6')-Ie-aph(2")-Ia, which encodes the bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2"). Found less commonly is aph(2")-Id, another gene recently reported to be associated with high-level gentamicin resistance in enterococci.

References

• Ref 1: Prodigious substrate specificity of AAC(6')-APH(2"), an aminoglycoside antibiotic resistance determinant in enterococci and staphylococci. Chem Biol. 1999 Feb;6(2):99-110. doi: 10.1016/S1074-5521(99)80006-4.
• Ref 2: The aacA-aphD gentamicin and kanamycin resistance determinant of Tn4001 from Staphylococcus aureus: expression and nucleotide sequence analysis. J Gen Microbiol. 1987 Nov;133(11):3039-52. doi: 10.1099/00221287-133-11-3039.
• Ref 3: Detection of the high-level aminoglycoside resistance gene aph(2")-Ib in Enterococcus faecium. Antimicrob Agents Chemother. 2000 Oct;44(10):2876-9. doi: 10.1128/AAC.44.10.2876-2879.2000.
• Ref 4: Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions. Pharmaceuticals (Basel). 2023 Feb 3;16(2):236.