Drug Information

Drug (ID: DG00031) and It's Reported Resistant Information

• Name: Spectinomycin
• Synonyms: Actinospectacin; Actinospectacina; Adspec; Espectinomicina; Prospec; SCM; SPCM; Spectam; Spectinomicina; Spectinomycine; Spectinomycinum; Spectogard; Stanilo; Togamycin; Trobicin; Actinospectacina [Italian]; Spectam Scour Halt; Spectinomicina [Italian]; Spectinomycin Di HCl; Spectinomycin HCl; Spectinomycin dihydrochloride; Spectinomycin hydrochloride; Spectinomycin hydrochloride anhydrous; Spectinomycin monohydrochloride; Spectinomycin sulfate; Antibiotic 2233wp; M 141; U 18409; U 18409 E; Actinospectacin, hydrochloride; Adspec (TN); Espectinomicina [INN-Spanish]; M-141; Prospec (TN); Spectinomycin (INN); Spectinomycin Dihydrochloride, Anhydrous; Spectinomycin Dihydrochloride, Pentahydrate; SpectinomycinHCl/ Sulphate; Spectinomycin Hydrochloride (anhydrous); Spectinomycin [INN:BAN]; Spectinomycine [INN-French]; Spectinomycinum [INN-Latin]; Trobicin (TN); U-18409AE; XK 43-1; Togamycin sulfate (1:1); ACTINOSPECTACIN, ESPECTINOMICINA, CHX-3101; (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)decahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4-one; (2R-(2alpha,4abeta,5abeta,6beta,7beta,8beta,9alpha,9aalpha,10abeta))-Decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-4H-pyrano(2,3-b)(1,4)benzodioxin-4-one monohydrochloride; 4H-Pyrano[2,3-b][1,4]benzodioxin-4-one, decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-, [2R-(2.alpha.,4a.beta.,5a.beta.,6.beta.,7.beta.,8.beta.,9.alpha.,9a.alpha.,10a.beta.)]-, sulfate (1:1) (salt)
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2], [3]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [4]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [5]
  Salmonellosis [ICD-11: 1A09]; [6]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (3 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [7]
  Pasteurellosis [ICD-11: 1B99]; [8]
  Respiratory trac infection [ICD-11: CA45]; [9]
• Target: Staphylococcus 30S ribosomal subunit (Stap-coc pbp2); F4NA87_STAAU; [3]
• Formula: C14H24N2O7
• IsoSMILES: C[C@@H]1CC(=O)[C@]2([C@@H](O1)O[C@@H]3[C@H]([C@@H]([C@@H]([C@@H]([C@H]3O2)NC)O)NC)O)O
• InChI: 1S/C14H24N2O7/c1-5-4-6(17)14(20)13(21-5)22-12-10(19)7(15-2)9(18)8(16-3)11(12)23-14/h5,7-13,15-16,18-20H,4H2,1-3H3/t5-,7-,8+,9+,10+,11-,12-,13+,14+/m1/s1
• InChIKey: UNFWWIHTNXNPBV-WXKVUWSESA-N
• PubChem CID: 15541
• ChEBI ID: CHEBI:9215
• TTD Drug ID: D02PCR
• INTEDE ID: DR2379
• DrugBank ID: DB00919

Type(s) of Resistant Mechanism of This Drug

  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

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Spectinomycin 9-adenylyltransferase (ANT) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus BD404; 1280
• In Vitro Model: Staphylococcus aureus RN4470; 1280
• In Vitro Model: Staphylococcus aureus RN4491; 1280
• In Vitro Model: Staphylococcus aureus RN4565; 1280
• In Vitro Model: Staphylococcus aureus RN4652; 1280
• In Vitro Model: Staphylococcus aureus RN4689; 1280
• In Vitro Model: Staphylococcus aureus RN4934; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The spc determinant encodes a unique adenyltransferase, AAD(9), that modifies spectinomycin but not streptomycin.

Key Molecule: Streptomycin 3''-adenylyltransferase (AADA27) [10]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Acinetobacter lwoffii VS15; 28090
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Pseudomonas sp. Tik3; 761262
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The genes aadA or ant(3")-1 encode streptomycin 3"-adenylyltransferase that mediates combined resistance to streptomycin and spectinomycin through an adenylation modification. aadA27 is a functionally active gene conferring high level of resistance to streptomycin and spectinomycin in the native A. lwoffii strain as well as in Escherichia coli.

Key Molecule: Spectinomycin 9-O-adenylyltransferase (ANT9) [11]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus ST398; 523796
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Downstream of the repN sequence was located a novel spectinomycin adenyltransferase gene, which was designated spd. The gene encoded a novel 257 amino acid protein, named Spd, which shared 47% identity with the spectinomycin adenyltransferase Aad9 from Enterococcus faecalis.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [12]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Vibrio fluvialis infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Vibrio fluvialis H-08942; 676
• Experiment for Molecule Alteration: PCR; DNA sequencing assay; Southern hybridization assay; Cloning and expression assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aac(3)-Id is a new type of aminoglycoside acetyltransferase gene which causes drug resistance.

Key Molecule: AADA9 protein (AADA9) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Corynebacterium glutamicum infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Corynebacterium glutamicum ATCC 13032; 196627
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: AadA9 is a novel aminoglycoside adenyltransferase gene cassette which lead to drug resistance.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside adenylyltransferase (AAD5) [7]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain 9516014-1; 562
• In Vitro Model: Escherichia coli strain k-12 J62-2; 83333
• In Vitro Model: Salmonella enterica serotype Typhimurium DT104 no. 9720921; 90371
• Experiment for Molecule Alteration: Sequencing with the QIAquick purification kit assay
• Experiment for Drug Resistance: Sensititre system assay
• Mechanism Description: The aadA genes are the only characterized genes that encode both streptomycin and spectinomycin resistance, and many of these genes are found as gene cassettes.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [5]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain k12; 83333
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nucleotide sequence of 1400 bp from R-plasmid R538-1 containing the streptomycin/spectinomycin adenyltransferase gene (aadA) was determined, and the location of the aadA gene was identified by a combination of insertion and deletion mutants. Its gene product, aminoglycoside 3"-adenylyltransferase (AAD(3")(9), has a Mr of 31,600.

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [6]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar typhimurium strain; 90371
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: Besides the genes present in the multidrug-resistant Salmonella serovar Typhimurium strains, other genes related to antibiotic resistance were described in Salmonella serovar Typhimurium or other closely related species. Tetracycline resistance could also be encoded by tetA, tetB, tetC or aadA21.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Catalase isozyme A/Tetracycline efflux MFS transporter/Dihydropteroate synthase (CATA1/TETB/SUL) [13]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella agona 231; 58095
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Disc diffusion assay
• Mechanism Description: The multiresistance plasmid from S. Agona strain 231 carried the chloramphenicol resistance gene catA1 coding for a type A chloramphenicol acetyltransferase and the resistance gene tet(B) coding for a tetracycline/minocycline exporter. This plasmid also harboured the streptomycin resistance gene strA coding for an aminoglycoside phosphotransferase and the sulphonamide resistance gene sul1 which represents part of the 3' conserved segment of class 1 integrons.

Pasteurellosis [ICD-11: 1B99]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [8]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Staphylococcus aureus ATCC 29213; 1280
• In Vitro Model: Pasteurella multocida 36950; 1075089
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The analysis of one representative P. multocida isolate identified an 82 kb integrative and conjugative element (ICE) integrated into the chromosomal DNA. This ICE, designated ICEPmu1, harboured 11 resistance genes, which confer resistance to streptomycin/spectinomycin (aadA25), streptomycin (strA and strB), gentamicin (aadB), kanamycin/neomycin (aphA1), tetracycline [tetR-tet(H)], chloramphenicol/florfenicol (floR), sulphonamides (sul2), tilmicosin/clindamycin [erm(42)] or tilmicosin/tulathromycin [msr(E)-mph(E)].

ICD-12: Respiratory system diseases

Respiratory trac infection [ICD-11: CA45]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pasteurella multocida infection [ICD-11: 1B99.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Mannheimia haemolytica infection [ICD-11: CA45.3]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

Key Molecule: Aminoglycoside (3'') (9) adenylyltransferase (AADA) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Histophilus somni infection [ICD-11: CA45.2]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli JM109 cells; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: AadA14 is the fifth reading frame in pCCk647 coded for a (3")(9) adenylyltransferase of 261 amino acids. The emergence of aada14 leads to drug resistance.

References

• Ref 1: Identification of the novel spectinomycin resistance gene spw in methicillin-resistant and methicillin-susceptible Staphylococcus aureus of human and animal origin. J Antimicrob Chemother. 2013 Jul;68(7):1679-80. doi: 10.1093/jac/dkt081. Epub 2013 Mar 19.
• Ref 2: Nucleotide sequence of a spectinomycin adenyltransferase AAD(9) determinant from Staphylococcus aureus and its relationship to AAD(3") (9). Mol Gen Genet. 1985;200(1):33-9. doi: 10.1007/BF00383309.
• Ref 3: Transposon Tn554: complete nucleotide sequence and isolation of transposition-defective and antibiotic-sensitive mutants. EMBO J. 1985 Dec 1;4(12):3357-65.
• Ref 4: The 27.8-kb R-plasmid pTET3 from Corynebacterium glutamicum encodes the aminoglycoside adenyltransferase gene cassette aadA9 and the regulated tetracycline efflux system Tet 33 flanked by active copies of the widespread insertion sequence IS6100. Plasmid. 2002 Sep;48(2):117-29. doi: 10.1016/s0147-619x(02)00120-8.
• Ref 5: Nucleotide sequence analysis of a gene encoding a streptomycin/spectinomycin adenylyltransferase. Plasmid. 1985 Jan;13(1):17-30. doi: 10.1016/0147-619x(85)90052-6.
• Ref 6: Evolution of antibiotic resistance in Salmonella enterica serovar typhimurium strains isolated in the Czech Republic between 1984 and 2002. Antimicrob Agents Chemother. 2003 Jun;47(6):2002-5. doi: 10.1128/AAC.47.6.2002-2005.2003.
• Ref 7: Novel streptomycin and spectinomycin resistance gene as a gene cassette within a class 1 integron isolated from Escherichia coli. Antimicrob Agents Chemother. 1999 Dec;43(12):3036-8. doi: 10.1128/AAC.43.12.3036.
• Ref 8: ICEPmu1, an integrative conjugative element (ICE) of Pasteurella multocida: analysis of the regions that comprise 12 antimicrobial resistance genes. J Antimicrob Chemother. 2012 Jan;67(1):84-90. doi: 10.1093/jac/dkr406. Epub 2011 Oct 14.
• Ref 9: Novel spectinomycin/streptomycin resistance gene, aadA14, from Pasteurella multocida. Antimicrob Agents Chemother. 2005 Jul;49(7):3046-9. doi: 10.1128/AAC.49.7.3046-3049.2005.
• Ref 10: The ancient small mobilizable plasmid pALWED1.8 harboring a new variant of the non-cassette streptomycin/spectinomycin resistance gene aadA27. Plasmid. 2016 Mar-May;84-85:36-43. doi: 10.1016/j.plasmid.2016.02.005. Epub 2016 Feb 16.
• Ref 11: Identification of a novel plasmid-associated spectinomycin adenyltransferase gene spd in methicillin-resistant Staphylococcus aureus ST398 isolated from animal and human sources. J Antimicrob Chemother. 2014 May;69(5):1193-6. doi: 10.1093/jac/dkt510. Epub 2014 Jan 8.
• Ref 12: New aminoglycoside acetyltransferase gene, aac(3)-Id, in a class 1 integron from a multiresistant strain of Vibrio fluvialis isolated from an infant aged 6 months. J Antimicrob Chemother. 2004 Jun;53(6):947-51. doi: 10.1093/jac/dkh221. Epub 2004 Apr 29.
• Ref 13: Class 1 integron-associated gene cassettes in Salmonella enterica subsp. enterica serovar Agona isolated from pig carcasses in Brazil. J Antimicrob Chemother. 2005 May;55(5):776-9. doi: 10.1093/jac/dki081. Epub 2005 Mar 10.