Drug Information

Drug (ID: DG00388) and It's Reported Resistant Information

• Name: Quinupristin/Dalfopristin
• Synonyms: Quinupristin-dalfopristin; Quinupristin - dalfopristin mixt; Synercid (TN); 126602-89-9; CHEBI:8733; C08034; D00854; Q1763990
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2]
  Staphylococcus meningitis [ICD-11: 1B54]; [3]
• Formula: C87H117N13O19S2
• IsoSMILES: CC[C@@H]1C(=O)N2CCC[C@H]2C(=O)N([C@H](C(=O)N3CC(C(=O)CC3C(=O)N[C@H](C(=O)O[C@@H]([C@@H](C(=O)N1)NC(=O)C4=C(C=CC=N4)O)C)C5=CC=CC=C5)CS[C@@H]6CN7CCC6CC7)CC8=CC=C(C=C8)N(C)C)C.CCN(CC)CCS(=O)(=O)[C@@H]1CCN2C1C(=O)O[C@@H]([C@@H](/C=C/C(=O)NC/C=C/C(=C/[C@H](CC(=O)CC3=NC(=CO3)C2=O)O)/C)C)C(C)C
• InChI: 1S/C53H67N9O10S.C34H50N4O9S/c1-6-37-50(68)61-23-11-14-38(61)51(69)59(5)40(26-32-16-18-36(19-17-32)58(3)4)52(70)62-28-35(30-73-43-29-60-24-20-33(43)21-25-60)42(64)27-39(62)47(65)57-45(34-12-8-7-9-13-34)53(71)72-31(2)44(48(66)55-37)56-49(67)46-41(63)15-10-22-54-46;1-7-37(8-2)16-17-48(44,45)28-13-15-38-31(28)34(43)47-32(22(3)4)24(6)11-12-29(41)35-14-9-10-23(5)18-25(39)19-26(40)20-30-36-27(21-46-30)33(38)42/h7-10,12-13,15-19,22,31,33,35,37-40,43-45,63H,6,11,14,20-21,23-30H2,1-5H3,(H,55,66)(H,56,67)(H,57,65);9-12,18,21-22,24-25,28,31-32,39H,7-8,13-17,19-20H2,1-6H3,(H,35,41)/b;10-9+,12-11+,23-18+/t31-,35 ,37-,38+,39 ,40+,43-,44+,45+;24-,25-,28-,31 ,32-/m11/s1
• InChIKey: PPKJUHVNTMYXOD-HVWWIRKTSA-N
• PubChem CID: 23724510

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: Ribosomal RNA large subunit methyltransferase (CFR ) [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 AS19; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Cfr confers resistance to antibiotics binding to the peptidyl transferase center on the ribosome.The primary product of the Cfr-mediated methylation is 8-methyladenosine (m8A), a new natural RNA modification that has so far not been seen at sites other than A2503 in 23S rRNA.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ABC transporter ATP-binding protein (ABCP) [1], [2]

• Molecule Alteration: Missense mutation; p.T450I
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Enterococcus faecium HM1070; 1352
• In Vitro Model: Enterococcus faecium UCN80; 1352
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: ABC systems constitute one of the largest families of proteins, with most of them being involved in import and export, often called ABC transporters.Several of these class 2 ABC systems have been involved in MLS resistance, such as Msr-, Vga-, or Lsa-like proteins.The observed profile of cross-resistance to lincosamides, streptogramins A, and pleuromutilins conferred by Eat(A)v was similar to those conferred by other Lsa-like proteins.

Staphylococcus meningitis [ICD-11: 1B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Virginiamycin B lyase (VGBB) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Spectrophotometric and fluorometric assay
• Mechanism Description: Virginiamycin B lyase (Vgb) inactivates the quinupristin component of Synercid by lactone ring opening and the enzyme promotes this reaction by intramolecular Beta-elimination without the involvement of a water molecule. Replacement of the conserved active site residues His228, Glu268, or His270 with alanine reduces or abolishes S. cohnii Vgb activity. Residue Lys285 in S. cohnii Vgb is spatially equivalent to the S. aureus Vgb active site residue Glu284.

References

• Ref 1: Comparative analysis of the first complete Enterococcus faecium genome. J Bacteriol. 2012 May;194(9):2334-41. doi: 10.1128/JB.00259-12. Epub 2012 Feb 24.
• Ref 2: Genetic basis for in vitro and in vivo resistance to lincosamides, streptogramins A, and pleuromutilins (LSAP phenotype) in Enterococcus faecium. Antimicrob Agents Chemother. 2013 Sep;57(9):4463-9. doi: 10.1128/AAC.01030-13. Epub 2013 Jul 8.
• Ref 3: Crystal structure and mechanism of the Staphylococcus cohnii virginiamycin B lyase (Vgb). Biochemistry. 2008 Apr 8;47(14):4257-65. doi: 10.1021/bi7015266. Epub 2008 Mar 15.
• Ref 4: Distinction between the Cfr methyltransferase conferring antibiotic resistance and the housekeeping RlmN methyltransferase. Antimicrob Agents Chemother. 2013 Aug;57(8):4019-26. doi: 10.1128/AAC.00448-13. Epub 2013 Jun 10.