Drug Information

Drug (ID: DG00373) and It's Reported Resistant Information

• Name: Gentamicin B
• Synonyms: Gentamicin B; BETAMICIN; 36889-15-3; Gentamycin B; UNII-67W9DGG4C7; 67W9DGG4C7; Sch 14342; (2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol; Betamicina; Betamicine; Betamicinum; Betamicin [INN]; Betamicine [INN-French]; Betamicinum [INN-Latin]; Betamicina [INN-Spanish]; SCHEMBL509198; CHEMBL2110604; ZINC8214501; Q27264175; (2R,3S,4S,5R,6R)-2-(aminomethyl)-6-((1R,2R,3S,4R,6S)-4,6-diamino-3-((2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yloxy)-2-hydroxycyclohexyloxy)tetrahydro-2H-pyran-3,4,5-triol; D-Streptamine, O-6-amino-6-deoxy-alpha-D-glucopyranosyl-(1-4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-6))-2-deoxy-; O-6-Amino-6-deoxy-alpha-D-glucopyranosyl-(1-4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L-arabinopyranosyl-(1-6))-2-deoxy-D-streptamine
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [3]
  Pneumonia [ICD-11: CA40]; [4]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [5]
• Formula: C19H38N4O10
• 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]([C@H]([C@@H]([C@H](O3)CN)O)O)O)N)N)O
• InChI: 1S/C19H38N4O10/c1-19(29)5-30-17(13(28)16(19)23-2)32-14-6(21)3-7(22)15(12(14)27)33-18-11(26)10(25)9(24)8(4-20)31-18/h6-18,23-29H,3-5,20-22H2,1-2H3/t6-,7+,8-,9-,10+,11-,12-,13-,14+,15-,16-,17-,18-,19+/m1/s1
• InChIKey: RHRAMPXHWHSKQB-GGEUKFTFSA-N
• PubChem CID: 11754987

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) [6]

• 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.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [7], [8], [9]

• 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 HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa PAe1100; 287
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: The AAC(3)-II AGRP is characterized by resistance to gentamicin, tobramycin, dibekacin, netilmicin, 2'-N-ethylnetilmicin, 6'-N-ethylnetilmicin, and sisomicin.

Key Molecule: Aminoglycoside adenyltransferase 2''-Ia (ANT2I) [10], [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: Acinetobacter baumannii AB5075; 1116234
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Etest assay
• Mechanism Description: ANT(2")-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2"-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core.

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Serratia marcescens infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

Key Molecule: Gentamicin 3'-acetyltransferase (AACC1) [1], [2]

• 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.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [5]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Escherichia coli strain XLI-Blue; 562
• In Vitro Model: Providencia stuartii strain PR50; 588
• In Vitro Model: Providencia stuartii strain SCH75082831A; 588
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Microdilution plates assay
• Mechanism Description: E.coli DH5alpha/pR 1000 demonstrated an AAC(2')-Ia resistance profile,with gentamicin, tobramycin, netilmicin, and 6'-Nethylnetilmicin MICs increased over those seen with E.coli DH5alpha. In addition, E.coli DH5alpha/pR 1000 did not show an elevated 2'-N-ethylnetilmicin MIC (MIC was 0.25ug/ml). Therefore, pR1000 encoded an enzyme capable of acetylating 6'-N-ethylnetilmicin but not 2'-N-ethylnetilmicin, suggesting 2'-N-acetyltransferase activity. DH5alpha/pSCH4500, which contains a subcloned 1.3-kb fragment, also demonstrated an AAC(2')-Ia resistance profile.

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Mycobacterium fortuitum infection [ICD-11: 1B2Z.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Streptomyces lividans strain 1326; 1200984
• In Vitro Model: Mycolicibacterium fortuitum strain FC1k; 1766
• In Vitro Model: Mycolicibacterium smegmatis strain mc2 155; 246196
• Experiment for Molecule Alteration: Southern blot hybridizations assay
• Experiment for Drug Resistance: Twofold dilution of antibiotics assay
• Mechanism Description: Thirty-four environmental and clinical isolates belonging to theM. fortuitumcomplex were chosen for the present study. The MICs of gentamicin varied, ranging from 2 to 16mg/ml. Crude extracts of all 34 strains were shown to have AAC activity. Acetylation of gentamicin, tobramycin, and kanamycins A and B was found for all the strains, showing a substrate profile consistent with the presence of an AAC(3) activity. Environmental isolateM. fortuitumFC1k was chosen for further studies because of its high level of AAC activity and the level of resistance to gentamicin (MIC, 16mg/ml).

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Mycobacterium smegmatis infection [ICD-11: 1B2Z.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Streptomyces lividans strain 1326; 1200984
• In Vitro Model: Mycolicibacterium fortuitum strain FC1k; 1766
• In Vitro Model: Mycolicibacterium smegmatis strain mc2 155; 246196
• Experiment for Molecule Alteration: Southern blot hybridizations assay
• Experiment for Drug Resistance: Twofold dilution of antibiotics assay
• Mechanism Description: The aac(2')-Ib gene cloned in a mycobacterial plasmid and introduced in Mycobacterium smegmatis conferred resistance to gentamicin, tobramycin, dibekacin, netilmicin, and 6'-N-ethylnetilmicin.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside 3'-phosphotransferase (A3AP) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Klebsiella pneumoniae infection [ICD-11: CA40.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• In Vitro Model: Escherichia coli strain 83-125; 562
• In Vitro Model: Escherichia coli strain 83-75; 562
• In Vitro Model: Escherichia coli strain JM83; 562
• In Vitro Model: Escherichia coli strain JM83(pRPG101); 562
• In Vitro Model: Escherichia coli strain M8820Mu; 562
• In Vitro Model: Escherichia coli strain MC1065; 562
• In Vitro Model: Escherichia coli strain MC1065(pRPG101); 562
• In Vitro Model: Escherichia coli strain POII1681; 562
• In Vitro Model: Escherichia coli strain PRC930(pAO43::Tn9O3); 562
• In Vitro Model: Klebsiella pneumoniae strains; 573
• In Vitro Model: Serratia marcescens strains; 615
• Experiment for Molecule Alteration: Restriction enzyme treating assay
• Experiment for Drug Resistance: Cation-supplemented Mueller-Hinton broth assay; agar dilution with MH agar assay
• Mechanism Description: Clinical isolates of Klebsiella pneumoniae and Serratia marcescens at a hospital that had used amikacin as its principal aminoglycoside for the preceding 42 months demonstrated high-level resistance to amikacin (greater than or equal to 256 micrograms/ml), kanamycin (greater than or equal to 256 micrograms/ml), gentamicin (greater than or equal to 64 micrograms/ml), netilmicin (64 micrograms/ml), and tobramycin (greater than or equal to 16 micrograms/ml). The clinical isolates and transformants produced a novel 3'-phosphotransferase, APH(3'), that modified amikacin and kanamycin in vitro.

References

• Ref 1: 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 2: 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.
• Ref 3: Characterization of the chromosomal aminoglycoside 2'-N-acetyltransferase gene from Mycobacterium fortuitum. Antimicrob Agents Chemother. 1996 Oct;40(10):2350-5. doi: 10.1128/AAC.40.10.2350.
• Ref 4: Isolation, characterization, and cloning of a plasmid-borne gene encoding a phosphotransferase that confers high-level amikacin resistance in enteric bacilli. Antimicrob Agents Chemother. 1988 Sep;32(9):1379-84. doi: 10.1128/AAC.32.9.1379.
• Ref 5: Characterization and transcriptional regulation of the 2'-N-acetyltransferase gene from Providencia stuartii. J Bacteriol. 1993 Oct;175(20):6492-8. doi: 10.1128/jb.175.20.6492-6498.1993.
• Ref 6: 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 7: Genes for gentamicin-(3)-N-acetyl-transferases III and IV. II. Nucleotide sequences of three AAC(3)-III genes and evolutionary aspects. Mol Gen Genet. 1985;198(3):514-20. doi: 10.1007/BF00332949.
• Ref 8: Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev. 1993 Mar;57(1):138-63. doi: 10.1128/mr.57.1.138-163.1993.
• Ref 9: A TEM-derived extended-spectrum beta-lactamase in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1996 Nov;40(11):2488-93. doi: 10.1128/AAC.40.11.2488.
• Ref 10: Structural and molecular basis for resistance to aminoglycoside antibiotics by the adenylyltransferase ANT(2")-Ia. mBio. 2015 Jan 6;6(1):e02180-14. doi: 10.1128/mBio.02180-14.
• Ref 11: Nucleotide sequence of the AAD(2'') aminoglycoside adenylyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538-1 and dhfrII in R388. Nucleic Acids Res. 1986 Nov 11;14(21):8625-35. doi: 10.1093/nar/14.21.8625.