Drug Information

Drug (ID: DG00094) and It's Reported Resistant Information

• Name: Netilmicin
• Synonyms: NTL; Netilmicina; Netilmicine; Netilmicinum; Netilyn; Netira; Nettacin; Vectacin; NETILMICIN SULFATE; Sch 20569; Netilmicin (INN); Netilmicin [INN:BAN]; Netilmicina [INN-Spanish]; Netilmicine [INN-French]; Netilmicinum [INN-Latin]; Netira (TN); Nettacin (TN); Sch-20569; O-(2,6-Diamino-2,3,4,6-tetradesoxy-alpha-glycero-4-hexenopyranosyl-(1-4)-O-(3-desoxy-4-C-methyl-3-methylamino-beta-L-arabinopyranosyl-(1-6)-2-desoxy-N1-ethyl-D-streptamin; (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4-amino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; (2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4-amino-3-[[3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; (2R,3S,4S,5S)-2-[(1S,2R,3S,4S,6R)-4-amino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; 1-N-Aethylsisomicin; 1-N-Ethylsisomicin; 2-[4-amino-3-[[3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol; 4-amino-3-{[3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy}-6-(ethylamino)-2-hydroxycyclohexyl 3-deoxy-4-c-methyl-3-(methylamino)pentopyranoside
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Corneal ulcer [ICD-11: 9A76]; [1], [2]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
  Folliculitis [ICD-11: 1B74]; [1], [2]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [4]
  Otitis media [ICD-11: AA80]; [1], [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
  Escherichia coli intestinal infection [ICD-11: 1A03]; [5]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [6]
• Target: Staphylococcus 30S ribosomal subunit (Stap-coc pbp2); F4NA87_STAAU; [1]
• Formula: C21H41N5O7
• IsoSMILES: CCN[C@@H]1C[C@@H]([C@H]([C@@H]([C@H]1O[C@@H]2[C@@H]([C@H]([C@@](CO2)(C)O)NC)O)O)O[C@@H]3[C@@H](CC=C(O3)CN)N)N
• InChI: 1S/C21H41N5O7/c1-4-26-13-7-12(24)16(32-19-11(23)6-5-10(8-22)31-19)14(27)17(13)33-20-15(28)18(25-3)21(2,29)9-30-20/h5,11-20,25-29H,4,6-9,22-24H2,1-3H3/t11-,12+,13-,14+,15-,16-,17+,18-,19-,20-,21+/m1/s1
• InChIKey: CIDUJQMULVCIBT-MQDUPKMGSA-N
• PubChem CID: 441306
• TTD Drug ID: D07JZF
• INTEDE ID: DR1139
• DrugBank ID: DB00955

Type(s) of Resistant Mechanism of This Drug

  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

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [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 ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Achromobacter xylosoxydans infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside acetyltransferase (AAC) [7]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Escherichia coli SCH92111602; 562
• Experiment for Molecule Alteration: Dot blot hybridizations assay
• Experiment for Drug Resistance: Standard broth microdilution method assay
• Mechanism Description: Escherichia coli SCH92111602 expresses an aminoglycoside resistance profile similar to that conferred by the aac(6')-Ie-aph(2")-Ia gene found in gram-positive cocci and was found to contain the aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im (only 44 nucleotides apart). SCH92111602 is an Escherichia coli clinical isolate resistant to a number of aminoglycoside antibiotics, including gentamicin, tobramycin, and amikacin, and contains an approximately 50-kb plasmid.

Key Molecule: Acetylpolyamine amidohydrolase (APAH) [3]

• 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; 668369
• In Vitro Model: Achromobacter xylosoxydans subsp. denitrificans AX-22; 85698
• In Vitro Model: Escherichia coli MkD-135; 562
• In Vitro Model: Pseudomonas aeruginosa 10145/3; 287
• Experiment for Molecule Alteration: DNA extraction and Sequencing assay
• Experiment for Drug Resistance: Macrodilution broth method assay
• Mechanism Description: The aphA15 gene is the first example of an aph-like gene carried on a mobile gene cassette, and its product exhibits close similarity to the APH(3')-IIa aminoglycoside phosphotransferase encoded by Tn5 (36% amino acid identity) and to an APH(3')-IIb enzyme from Pseudomonas aeruginosa (38% amino acid identity). Expression of the cloned aphA15 gene in Escherichia coli reduced the susceptibility to kanamycin and neomycin as well as (slightly) to amikacin, netilmicin, and streptomycin.

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) [6]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Mycobacterium smegmatis infection [ICD-11: 1B2Z.3]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain DH5a; 668369
• In Vitro Model: Mycolicibacterium smegmatis strain EP10; 1772
• In Vitro Model: Mycolicibacterium smegmatis strain mc2155; 246196
• Experiment for Molecule Alteration: Southern blot hybridizations assay
• Experiment for Drug Resistance: Agar macrodilution assay
• Mechanism Description: The introduction of a plasmid-located copy of either the aac (2')-Ib or the aac (2')-Id genes into M. smegmatis mc2155 produces an increase in the level of resistance over those values observed in M. smegmatis mc2155. However, the introduction of the plasmid-located aac (2') Ic gene did not lead to an increase in the MICs. In this experiment, an increase of at least two dilutions in the MIC values over those observed in M. smegmatismc2155 with the vector pSUM36 has been assumed to be due to the increase in the activity of the AAC (2') enzyme. The MICs for the 2'-ethylnetilmicin do not change since this aminoglycoside is not a substrate of the AAC (2') enzyme.

Key Molecule: Aminoglycoside 2'-N-acetyltransferase (A2NA) [4]

• 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.

Folliculitis [ICD-11: 1B74]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Folliculitis [ICD-11: 1B74.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

ICD-09: Visual system diseases

Corneal ulcer [ICD-11: 9A76]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Corneal ulcers [ICD-11: 9A76.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

ICD-10: Ear/mastoid process diseasess

Otitis media [ICD-11: AA80]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aminoglycoside N(3)-acetyltransferase (AACC2) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pseudomonas aeruginosa infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli ATCC 25922; 1322345
• In Vitro Model: Pseudomonas aeruginosa ATCC 27853; 287
• In Vitro Model: Pseudomonas aeruginosa isolates; 287
• In Vitro Model: Staphylococcus aureus ATCC 25923; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Various aminoglycoside modifying enzymes were associated with overlapping phenotypes: 36.5% strains produced AAC(6')-I with either a serine (GEN-TOB-NET) or a leucine (TOB-NET-AMk) at position 119, or both variants (GEN-TOB-NET-AMk); 21.2% expressed ANT(2")-I (GEN-TOB), 7.7% AAC(3)-II (GEN-TOB-NET), 5.8% AAC(3)-I (GEN) and 1.9% AAC(6')-II (GEN-TOB-NET-AMk) or AACA7 (TOB-NET-AMk).

References

• Ref 1: Beta-lactam and aminoglycoside resistance rates and mechanisms among Pseudomonas aeruginosa in French general practice (community and private healthcare centres). J Antimicrob Chemother. 2008 Aug;62(2):316-23. doi: 10.1093/jac/dkn174. Epub 2008 May 8.
• Ref 2: 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 3: In70 of plasmid pAX22, a bla(VIM-1)-containing integron carrying a new aminoglycoside phosphotransferase gene cassette. Antimicrob Agents Chemother. 2001 Apr;45(4):1249-53. doi: 10.1128/AAC.45.4.1249-1253.2001.
• Ref 4: 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 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: Aminoglycoside 2'-N-acetyltransferase genes are universally present in mycobacteria: characterization of the aac(2')-Ic gene from Mycobacterium tuberculosis and the aac(2')-Id gene from Mycobacterium smegmatis. Mol Microbiol. 1997 Apr;24(2):431-41. doi: 10.1046/j.1365-2958.1997.3471717.x.
• Ref 7: Aminoglycoside resistance genes aph(2")-Ib and aac(6')-Im detected together in strains of both Escherichia coli and Enterococcus faecium. Antimicrob Agents Chemother. 2001 Oct;45(10):2691-4. doi: 10.1128/AAC.45.10.2691-2694.2001.