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
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Investigative; [1], [2]
• 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 (3 diseases)
  Pancreatic cancer [ICD-11: 2C10]; [4]
  Actinomycetoma [ICD-11: 1C43]; [5]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2]
• Target: Bacterial 23S ribosomal RNA (Bact 23S rRNA); NOUNIPROTAC; [1]
• 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

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]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• 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]

• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Molecule Alteration: Expression; Up-regulation
• 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.

Actinomycetoma [ICD-11: 1C43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (adenosine(1067)-2'-O)-methyltransferase (TSNR) [5]

• Resistant Disease: Streptomyces laurentii infection [ICD-11: 1C43.9]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain XL-1 Blue MRF; 562
• In Vitro Model: Streptomyces laurentii strain; 39478
• In Vitro Model: 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) [5]

• Resistant Disease: Streptomyces lividans infection [ICD-11: 1C43.8]
• Molecule Alteration: Expression; Acquired
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain XL-1 Blue MRF; 562
• In Vitro Model: Streptomyces laurentii strain; 39478
• In Vitro Model: 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]

• Resistant Disease: Streptomyces azureus infection [ICD-11: 1C43.4]
• Molecule Alteration: Expression; Inherence
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain ED8767; 562
• In Vitro Model: Streptomyces lividans strain M252; 1916
• In Vitro Model: Streptomyces lividans strain 66; 1200984
• In Vitro Model: Escherichia coli strain W5445; 562
• In Vitro Model: Streptomyces lividans strain M264; 1916
• In Vitro Model: 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.

ICD-02: Benign/in-situ/malignant neoplasm

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Forkhead box protein M1 (FOXM1) [4]

• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expressiom; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: nude mice injected Panc-1 cells; Mus musculus
• Experiment for Drug Resistance: Tumor evaluation assay
• Mechanism Description: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.

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: Huaier enhances the tumor-killing effect and reverses gemcitabine-induced stemness by suppressing FoxM1. Phytomedicine. 2024 Jul;129:155656.
• Ref 5: 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.