Drug Information

Drug (ID: DG00369) and It's Reported Resistant Information

• Name: Gentamicin C
• Synonyms: Gentamicin C; 11097-82-8; (2R,3S,4R,5R)-2-[(1S,2R,3R,4S,6R)-4,6-diamino-3-[(2R,3R,6S)-3-amino-6-(aminomethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; Gentamicin C complex
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
• Formula: C19H39N5O7
• 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@H](O3)CN)N)N)N)O
• InChI: 1S/C19H39N5O7/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/h8-18,24-27H,3-7,20-23H2,1-2H3/t8-,9+,10-,11+,12+,13-,14+,15-,16+,17+,18+,19-/m0/s1
• InChIKey: VEGXETMJINRLTH-ALRICIOSSA-N
• PubChem CID: 3084091

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) [4]

• 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) [5], [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 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) [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: 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: AAC(6')-Ib family aminoglycoside 6'-N-acetyltransferase (AAC6IB) [1]

• 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 DH10B; 316385
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli k-12; 83333
• In Vitro Model: Pseudomonas aeruginosa Pa695; 287
• Experiment for Molecule Alteration: PCR experiments assay
• Experiment for Drug Resistance: Disk diffusion method assay
• Mechanism Description: The fusion product was functional, as was the product of each gene cloned separately: AAC(3)-I, despite the deletion of the four last amino acids, and AAC(6"), which carried three amino acid changes compared with the most homologous sequence. The AAC(3)-I protein conferred an expected gentamicin and fortimicin resistance, and the AAC(6"), despite the Leu-119-Ser substitution, yielded resistance to kanamycin, tobramycin, and dibekacin, but slightly affected netilmicin and amikacin, and had no apparent effect on gentamicin. The fusion product conveyed a large profile of resistance, combining the AAC(6") activity with a higher level of gentamicin resistance without accompanying fortimicin resistance.

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

• 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) [2]

• 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) [2]

• 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.

References

• Ref 1: Molecular characterization of a novel class 1 integron containing bla(GES-1) and a fused product of aac3-Ib/aac6'-Ib' gene cassettes in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2002 Mar;46(3):638-45. doi: 10.1128/AAC.46.3.638-645.2002.
• Ref 2: 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 3: 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 4: 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 5: 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 6: 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 7: 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 8: 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 9: 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.
• Ref 10: 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 11: 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.