Drug Information

Drug (ID: DG00188) and It's Reported Resistant Information
Name
Thiostrepton
Synonyms
Thiostrepton; Thiostrepton from Streptomyces azureus; Bryamycin; Thiactin; Alaninamide,; 1393-48-2; NSC81722; NSC170365; NSC 81722; NSC 170365; CHEMBL1981887; CHEBI:94340; MolPort-003-939-599; NSC-81722; NSC-170365; NCGC00485235-01; Thiostrepton from Streptomyces azureus, &gt
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Indication
In total 1 Indication(s)
Discovery agent [ICD-11: N.A.]
Investigative
[1], [2]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Actinomycetoma [ICD-11: 1C43]
[3]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
Actinomycetoma [ICD-11: 1C43]
[4]
Bacterial infection [ICD-11: 1A00-1C4Z]
[1], [2]
Target Bacterial 23S ribosomal RNA (Bact 23S rRNA) NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C72H85N19O18S5
IsoSMILES
CCC(C)C1C(=O)NC(C(=O)NC(=C)C(=O)NC(C(=O)NC23CCC(=NC2C4=CSC(=N4)C(C(OC(=O)C5=NC6=C(C=CC(C6O)N1)C(=C5)C(C)O)C)NC(=O)C7=CSC(=N7)C(NC(=O)C8CSC(=N8)/C(=C\\C)/NC(=O)C(NC(=O)C9=CSC3=N9)C(C)O)C(C)(C(C)O)O)C1=NC(=CS1)C(=O)NC(=C)C(=O)NC(=C)C(=O)N)C)C
InChI
1S/C72H85N19O18S5/c1-14-26(3)47-63(105)78-30(7)57(99)75-28(5)56(98)76-31(8)58(100)91-72-19-18-40(66-85-43(22-111-66)59(101)77-29(6)55(97)74-27(4)54(73)96)81-52(72)42-21-112-67(83-42)49(34(11)109-69(107)41-20-37(32(9)92)36-16-17-39(79-47)51(95)50(36)80-41)89-60(102)44-24-113-68(86-44)53(71(13,108)35(12)94)90-62(104)45-23-110-65(84-45)38(15-2)82-64(106)48(33(10)93)88-61(103)46-25-114-70(72)87-46/h15-17,20-22,24-26,30-35,39,45,47-49,51-53,79,92-95,108H,4-6,14,18-19,23H2,1-3,7-13H3,(H2,73,96)(H,74,97)(H,75,99)(H,76,98)(H,77,101)(H,78,105)(H,82,106)(H,88,103)(H,89,102)(H,90,104)(H,91,100)/b38-15+
InChIKey
NSFFHOGKXHRQEW-DVRIZHICSA-N
PubChem CID
16129666
TTD Drug ID
D0G5FV
DrugBank ID
DB11467
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-01: Infectious/parasitic diseases
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Bacterial infection [ICD-11: 1A00-1C4Z]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: rRNA methyltransferase PikR1 (PIKR1) [1], [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Bacterial infection [ICD-11: 1A00-1C4Z]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli 668369
Escherichia coli BL21(DE3) 469008
Escherichia coli BL21(DE3)pLysS 866768
Escherichia coli S17-1 1227813
Streptomyces antibioticus ATCC 11891 1890
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
 Molecule Info 
Resistant Disease Bacterial infection [ICD-11: 1A00-1C4Z]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli 668369
Escherichia coli BL21(DE3) 469008
Escherichia coli BL21(DE3)pLysS 866768
Escherichia coli S17-1 1227813
Streptomyces antibioticus ATCC 11891 1890
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.
Actinomycetoma [ICD-11: 1C43]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [4]
Molecule Alteration Expression
Inherence
 Molecule Info 
Resistant Disease Streptomyces laurentii infection [ICD-11: 1C43.9]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain XL-1 Blue MRF 562
Streptomyces laurentii strain 39478
Streptomyces lividans strain Tk24 457428
Experiment for
Molecule Alteration		 DNA hybridizations assay
Mechanism Description The Th R (tsnR) gene from SI is highly similar to the Th R and Nh R genes from Saz and Sac. Partial nt sequence analysis of the DNA flanking the Sl tsnR gene indicates that tsnR is clustered with r-protein operons. Insert-directed integration of pkCl132 within this region supports the idea that, in S1, tsnR is not clustered with genes encoding Th biosynthetic enzymes.
Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [4]
Molecule Alteration Expression
Acquired
 Molecule Info 
Resistant Disease Streptomyces lividans infection [ICD-11: 1C43.8]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain XL-1 Blue MRF 562
Streptomyces laurentii strain 39478
Streptomyces lividans strain Tk24 457428
Experiment for
Molecule Alteration		 DNA hybridizations assay
Mechanism Description The Th R (tsnR) gene from SI is highly similar to the Th R and Nh R genes from Saz and Sac. Partial nt sequence analysis of the DNA flanking the Sl tsnR gene indicates that tsnR is clustered with r-protein operons. Insert-directed integration of pkCl132 within this region supports the idea that, in S1, tsnR is not clustered with genes encoding Th biosynthetic enzymes.
Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [3]
Molecule Alteration Expression
Inherence
 Molecule Info 
Resistant Disease Streptomyces azureus infection [ICD-11: 1C43.4]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli JM109 562
Escherichia coli strain ED8767 562
Streptomyces lividans strain M252 1916
Streptomyces lividans strain 66 1200984
Escherichia coli strain W5445 562
Streptomyces lividans strain M264 1916
Streptomyces lividans strain M274 1916
Experiment for
Molecule Alteration		 DNA sequencing assay
Mechanism Description Promoter-probe plasmid vectors were used to isolate putative promoter-containing DNA fragments of three Streptomyces antibiotic resistance genes, the rRNA methylase (tsr) gene of S. azureus, the aminoglycoside phosphotransferase (aph) gene of S. fradiae, and the viomycin phosphotransferase (vph) gene of S. vinaceus. The rRNA methylase (tsr) gene of S. azureus, which confers resistance to thiostrepton by methylation of 23S rRNA.
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 Nucleotide sequences encoding and promoting expression of three antibiotic resistance genes indigenous to Streptomyces. Mol Gen Genet. 1985;199(1):26-36. doi: 10.1007/BF00327505.
Ref 4 The thiostrepton-resistance-encoding gene in Streptomyces laurentii is located within a cluster of ribosomal protein operons. Gene. 1995 Oct 16;164(1):137-42. doi: 10.1016/0378-1119(95)00442-9.

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