Drug Information

Drug (ID: DG00379) and It's Reported Resistant Information

• Name: Pristinamycin IA
• Synonyms: Pristinamycin IA; Streptogramin B; Ostreogrycin B; Antibiotic PA 114B; NSC 92554; UNII-V50XJ0NC3I; V50XJ0NC3I; CHEBI:8417; Mikamycin IA; 3131-03-1; Virginiamycin B; Vernamycin BA; Vernamycin B alpha; N-((6R,9S,10R,13S,15aS,22S,24aS)-22-(4-(dimethylamino)benzyl)-6-ethyl-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1]oxa[4,7,10,13,16]pentaazacyclononadecin-9-yl)-3-hydroxypicolinamide; 4-(4-(Dimethylamino)-N-methyl-L-phenylalanine)virginiamycin S1; 4-[4-(Dimethylamino)-N-methyl-L-phenylalanine]virginiamycin S1; PA 114B; Antibiotic PA 114B1; Antibiotic PA 114 B1; CHEMBL1256399; SCHEMBL13176900; HY-A0279A; C45H54N8O10; ZINC9574677; CS-5850; BRN 0078387; X8445; 4-27-00-09718 (Beilstein Handbook Reference); J-018376; Q14035740; UNII-4O8O7Q7IU4 component YGXCETJZBDTKRY-DZCVGBHJSA-N; UNII-JN6G9U5358 component YGXCETJZBDTKRY-DZCVGBHJSA-N; Virginiamycin S1, 4-(4(dimethylamino)-N-methyl-L-phenylalanine)-; Vernamycin Balpha; Virginiamycin S1, 4-(4-(dimethylamino)-N-methyl-L-phenylalanine)- (9CI); N-[(3S,6S,12R,15S,16R,19S,22S)-3-[[4-(dimethylamino)phenyl]methyl]-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptaoxo-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.06,10]hexacosan-15-yl]-3-hydroxypyridine-2-carboxamide; N-[(6R,9S,10R,13S,15aS,22S,24aS)-22-{[4-(dimethylamino)phenyl]methyl}-6-ethyl-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyldocosahydro-12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]oxapentaazacyclononadecin-9-yl]-3-hydroxypyridine-2-carboxamide
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Bacillus infection [ICD-11: 1C4Y]; [1]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2], [3], [4]
  Staphylococcus meningitis [ICD-11: 1B54]; [5]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Clostridioides difficile intestinal infection [ICD-11: 1A04]; [6]
• Formula: C45H54N8O10
• IsoSMILES: CC[C@@H]1C(=O)N2CCC[C@H]2C(=O)N([C@H](C(=O)N3CCC(=O)C[C@H]3C(=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)CC6=CC=C(C=C6)N(C)C)C
• InChI: 1S/C45H54N8O10/c1-6-31-42(59)52-22-11-14-32(52)43(60)51(5)34(24-27-16-18-29(19-17-27)50(3)4)44(61)53-23-20-30(54)25-33(53)39(56)49-37(28-12-8-7-9-13-28)45(62)63-26(2)36(40(57)47-31)48-41(58)38-35(55)15-10-21-46-38/h7-10,12-13,15-19,21,26,31-34,36-37,55H,6,11,14,20,22-25H2,1-5H3,(H,47,57)(H,48,58)(H,49,56)/t26-,31-,32+,33+,34+,36+,37+/m1/s1
• InChIKey: YGXCETJZBDTKRY-DZCVGBHJSA-N
• PubChem CID: 11136668
• DrugBank ID: DB13704

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

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) [2], [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 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.

Key Molecule: 23S rRNA (Adenine(2503)-C(8))-methyltransferase ClbA (CIBA) [7]

• 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 JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Colibactin polyketide synthase ClbC (CLBC) [7]

• 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 JW2501-1; 562
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes.Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene.The Cfr-like proteins ClbA, ClbC, and ClbB confer a resistance pattern similar to that of the Cfr methyltransferase.

Clostridioides difficile intestinal infection [ICD-11: 1A04]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: rRNA adenine N-6-methyltransferase (ErmB) [6]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Clostridium difficile infection [ICD-11: 1A04.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The cellular methylation in C. difficile has been proposed to induce resistance to macrolides (erythromycin, ERY), lincosamide (clindamycin) and streptogramin B antibiotic family. These drugs target at a bacterial 50S ribosomal subunit, causing the inhibition of peptide chain growth by blocking the movement of ribosome. ERY ribosomal methylase B (ErmB) is responsible for ribosomal methylation at the specific site of 23S rRNA, resulting in the prevention of antibiotic binding.

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) [5]

• 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).

Bacillus infection [ICD-11: 1C4Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm34 (ERM34) [1]

• Molecule Alteration: Methylation; Ribosomal methylation
• Resistant Disease: Bacillus clausii infection [ICD-11: 1C4Y.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus clausii ATCC 21536; 79880
• Experiment for Molecule Alteration: Cloning experiments and gene seqencing assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: This pattern of resistance generally due to the presence of an erm gene encoding a ribosomal methylase.

References

• Ref 1: Characterization of a new erm-related macrolide resistance gene present in probiotic strains of Bacillus clausii. Appl Environ Microbiol. 2004 Jan;70(1):280-4. doi: 10.1128/AEM.70.1.280-284.2004.
• Ref 2: 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 3: 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 4: 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 5: 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 6: Insights into drug resistance mechanisms in Clostridium difficile .Essays Biochem. 2017 Mar 3;61(1):81-88. doi: 10.1042/EBC20160062. Print 2017 Feb 28. 10.1042/EBC20160062
• Ref 7: The order Bacillales hosts functional homologs of the worrisome cfr antibiotic resistance gene. Antimicrob Agents Chemother. 2012 Jul;56(7):3563-7. doi: 10.1128/AAC.00673-12. Epub 2012 Apr 30.