Drug Information

Drug (ID: DG00370) and It's Reported Resistant Information

• Name: Sisomicin
• Synonyms: Sisomicin; Rickamicin; Sisomycin; 32385-11-8; Sissomicin; Antibiotic 6640; Antibiotic 66-40; Sch 13475; Dehydrogentamicin Cla; Sch-13475; UNII-X55XSL74YQ; X55XSL74YQ; CHEBI:9169; Sisomin; D-Streptamine, O-3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-6)-O-(2,6-diamino-2,3,4,6-tetradeoxy-alpha-D-glycero-hex-4-enopyranosyl-(1-4))-2-deoxy-; Sisomicinum; Sisomicina; Sisomicine; (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; Sch 13475 sulfate; Sisomicine [INN-French]; Sisomicinum [INN-Latin]; Salvamina; Sisomicina [INN-Spanish]; Siseptin sulfate; (1S,2S,3R,4S,6R)-4,6-diamino-3-[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yloxy]-2-hydroxycyclohexyl 3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranoside; (1s,2s,3r,4s,6r)-4,6-Diamino-3-{[(2s,3r)-3-Amino-6-(Aminomethyl)-3,4-Dihydro-2h-Pyran-2-Yl]oxy}-2-Hydroxycyclohexyl 3-Deoxy-4-C-Methyl-3-(Methylamino)-Beta-L-Arabinopyranoside; (2R,3R,4R,5R)-2-(((1S,2S,3R,4S,6R)-4,6-diamino-3-(((2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl)oxy)-2-hydroxycyclohexyl)oxy)-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol; O-2,6-Diamino-2,3,4,6-tetradeoxy-alpha-D-glycero-hex-4-enopyranosyl-(1-4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-6))-2-deoxy-D-streptamine; C19H37N5O7; EINECS 251-018-2; BRN 1357913; Sisomicin [USAN:INN:BAN]; Sch13475; sisomicin-sulfate; SiS; SISO; Sisomicin (USAN/INN); SCHEMBL49395; O-2,6-Diamino-2,3,4,6-tetradeoxy-alpha-D-glycero-hex-4-enopyranosyl-(1-4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-6)-2-deoxy-D-streptamine; O-3-Deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-4)-O-(2,6-diamino-2,3,4,6-tetradeoxy-alpha-D-glycero-hex-4-enopyranosyl-(1-6))-2-deoxy-L-streptamine; CHEMBL221886; GTPL10858; ZINC56870809; AKOS015895179; DB12604; (2S-cis)-4-O-(3-Amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl)-2-deoxy-6-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl)-D-streptamine; 85S118; C00494; D02544; Q3962119; (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxy-cyclohexoxy]-5-methyl-4-(methylamino)tetrahydropyran-3,5-diol; (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[[3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (7 diseases)
  Bacterial genitourinary infection [ICD-11: GA0Z-GC8Z]; [1]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  Gram-negative bacterial infection [ICD-11: 1B74-1G40]; [1]
  Infective endocarditis [ICD-11: BB40]; [1]
  Peritonitis [ICD-11: DC50]; [1]
  Respiratory trac infection [ICD-11: CA45]; [1]
  Sepsis [ICD-11: 1G40]; [1]
• Formula: C19H37N5O7
• IsoSMILES: C[C@@]1(CO[C@@H]([C@@H]([C@H]1NC)O)O[C@H]2[C@@H](C[C@@H]([C@H]([C@@H]2O)O[C@@H]3[C@@H](CC=C(O3)CN)N)N)N)O
• InChI: 1S/C19H37N5O7/c1-19(27)7-28-18(13(26)16(19)24-2)31-15-11(23)5-10(22)14(12(15)25)30-17-9(21)4-3-8(6-20)29-17/h3,9-18,24-27H,4-7,20-23H2,1-2H3/t9-,10+,11-,12+,13-,14-,15+,16-,17-,18-,19+/m1/s1
• InChIKey: URWAJWIAIPFPJE-YFMIWBNJSA-N
• PubChem CID: 36119
• INTEDE ID: DR2408
• DrugBank ID: DB12604

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

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: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [3]

• Molecule Alteration: Methylation; p.M7G1405
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: Protein-RNA footprinting assay
• Experiment for Drug Resistance: Isothermal titration calorimetry assay
• Mechanism Description: Sgm methylates G1405 in 16S rRNA to m7G, thereby rendering the ribosome resistant to 4, 6-disubstituted deoxystreptamine aminoglycosides.

Key Molecule: 16S rRNA (guanine(1405)-N(7))-methyltransferase (RMTA) [4]

• Molecule Alteration: Expression; Intergeneric lateral gene transfer
• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa AR-2; 287
• Experiment for Molecule Alteration: PCR screening assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The 16S rRNA methylase gene has undergone intergeneric horizontal gene transfer from some aminoglycoside producing microorganisms to Pseudomonas aeruginosa, which is called rmtA. rmtA protect bacterial 16S rRNA from intrinsic aminoglycosides by methylation.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(6')-acetyltransferase type 1 (A6AC1) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pseudomonas aeruginosa PAO1; 208964
• In Vitro Model: Pseudomonas aeruginosa Nk0001; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0002; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0003; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0004; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0005; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0006; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0007; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0008; 287
• In Vitro Model: Pseudomonas aeruginosa Nk0009; 287
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Micro-dilution method assay
• Mechanism Description: Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin.AAC(6')-Iag is a functional acetyltransferase that modifies alternate amino groups on the AGs.

Key Molecule: Aminoglycoside acetyltransferase (AAC) [2]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• Experiment for Molecule Alteration: PCR mapping and sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: Aac(3)-Ic gene could contribute to aminoglycoside resistance with a pattern typical of AAC(3)-I enzymes.

Key Molecule: Gentamicin 3'-acetyltransferase (AACC1) [6], [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 strain BN; 562
• In Vitro Model: Escherichia coli strain J62; 562
• In Vitro Model: Escherichia coli strain k12 W3110; 83333
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: The most common mechanisms of resistance to aminoglycoside-aminocyclitol (AG) antibiotics in bacteria are exerted by enzymatic modification which results in failure of their binding to ribosomal targets and in prevention of uptake by the cell.

Gram-negative bacterial infection [ICD-11: 1B74-1G40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

Sepsis [ICD-11: 1G40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Sepsis [ICD-11: 1G40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

ICD-11: Circulatory system diseases

Infective endocarditis [ICD-11: BB40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Infective endocarditis [ICD-11: BB40.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

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: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Respiratory trac infection [ICD-11: CA45.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

ICD-13: Digestive system diseases

Peritonitis [ICD-11: DC50]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

ICD-16: Genitourinary system diseases

Bacterial genitourinary infection [ICD-11: GA0Z-GC8Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Bifunctional AAC/APH (AAC/APH) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gram-negative pathogens infection [ICD-11: 1B74-1G40]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• In Vitro Model: Escherichia coli JM83; 562
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Aminoglycoside 2"-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci.APH(2")-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin.

References

• Ref 1: Novel aminoglycoside 2''-phosphotransferase identified in a gram-negative pathogen. Antimicrob Agents Chemother. 2013 Jan;57(1):452-7. doi: 10.1128/AAC.02049-12. Epub 2012 Nov 5.
• Ref 2: Novel 3-N-aminoglycoside acetyltransferase gene, aac(3)-Ic, from a Pseudomonas aeruginosa integron. Antimicrob Agents Chemother. 2003 May;47(5):1746-8. doi: 10.1128/AAC.47.5.1746-1748.2003.
• Ref 3: Structural basis for the methylation of G1405 in 16S rRNA by aminoglycoside resistance methyltransferase Sgm from an antibiotic producer: a diversity of active sites in m7G methyltransferases. Nucleic Acids Res. 2010 Jul;38(12):4120-32. doi: 10.1093/nar/gkq122. Epub 2010 Mar 1.
• Ref 4: Acquisition of 16S rRNA methylase gene in Pseudomonas aeruginosa. Lancet. 2003 Dec 6;362(9399):1888-93. doi: 10.1016/S0140-6736(03)14959-8.
• Ref 5: Identification and characterization of a novel aac(6')-Iag associated with the blaIMP-1-integron in a multidrug-resistant Pseudomonas aeruginosa. PLoS One. 2013 Aug 12;8(8):e70557. doi: 10.1371/journal.pone.0070557. eCollection 2013.
• Ref 6: Characterization of two aminoglycoside-(3)-N-acetyltransferase genes and assay as epidemiological probes. J Antimicrob Chemother. 1991 Sep;28(3):333-46. doi: 10.1093/jac/28.3.333.
• Ref 7: On the evolution of Tn21-like multiresistance transposons: sequence analysis of the gene (aacC1) for gentamicin acetyltransferase-3-I(AAC(3)-I), another member of the Tn21-based expression cassette. Mol Gen Genet. 1989 Jun;217(2-3):202-8. doi: 10.1007/BF02464882.