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Identification
NameNetilmicin
Accession NumberDB00955  (APRD00232)
TypeSmall Molecule
GroupsApproved
Description

Netilmicin is a semisynthetic 1-N-ethyl derivative of sisomycin, an aminoglycoside antibiotic with action similar to gentamicin, but less ear and kidney toxicity. [PubChem] Netilmicin inhibits protein synthesis in susceptible organisms by binding to the bacterial 30S ribosomal subunit and interfering with mRNA binding and the acceptor tRNA site. The bactericidal effect of netilmiicin is not fully understood.

Structure
Thumb
Synonyms
1-N-Ethylsisomicin
Netilmicin
Netilmycin
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-N(1)-ethyl-D-streptamine
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Netromycin Inj 100mg/mlsolution100 mgintramuscular; intravenousSchering Plough Canada Inc1981-12-312004-07-21Canada
Netromycin Inj 50mg/mlsolution50 mgintramuscular; intravenousSchering Plough Canada Inc1981-12-312004-07-21Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
NetromycinNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Netilmicin sulfate
ThumbNot applicableDBSALT001164
Categories
UNII4O5J85GJJB
CAS number56391-56-1
WeightAverage: 475.5795
Monoisotopic: 475.300598691
Chemical FormulaC21H41N5O7
InChI KeyInChIKey=ZBGPYVZLYBDXKO-HILBYHGXSA-N
InChI
InChI=1S/C21H41N5O7/c1-4-26-13-7-12(24)16(32-19-11(23)6-5-10(8-22)31-19)15(28)17(13)33-20-21(2,29)18(25-3)14(27)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
IUPAC Name
(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}-3-methyl-4-(methylamino)oxane-3,5-diol
SMILES
CCN[C@@H]1C[[email protected]](N)[C@@H](O[[email protected]]2OC(CN)=CC[[email protected]]2N)[[email protected]](O)[[email protected]]1O[[email protected]]1OC[[email protected]](O)[C@@H](NC)[C@@]1(C)O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as aminoglycosides. These are molecules or a portion of a molecule composed of amino-modified sugars.
KingdomOrganic compounds
Super ClassOrganooxygen compounds
ClassCarbohydrates and carbohydrate conjugates
Sub ClassAminosaccharides
Direct ParentAminoglycosides
Alternative Parents
Substituents
  • Aminoglycoside core
  • Glucosamine
  • Amino sugar
  • O-glycosyl compound
  • Glycosyl compound
  • Cyclohexylamine
  • Cyclohexanol
  • Oxane
  • Monosaccharide
  • Tertiary alcohol
  • Cyclic alcohol
  • Secondary alcohol
  • 1,2-aminoalcohol
  • Oxacycle
  • Organoheterocyclic compound
  • Secondary amine
  • Secondary aliphatic amine
  • Acetal
  • Hydrocarbon derivative
  • Primary amine
  • Organonitrogen compound
  • Primary aliphatic amine
  • Amine
  • Alcohol
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of bacteremia, septicaemia, respiratory tract infections, skin and soft-tissue infection, burns, wounds, and peri-operative infections caused by susceptible strains.
PharmacodynamicsNetilmicin is a semisynthetic, water soluble antibiotic of the aminoglycoside group, produced by the fermentation of Micromonospora inyoensis, a species of actinomycete. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. It is active at low concentrations against a wide variety of pathogenic bacteria including Escherichia coli, bacteria of the Klebsiella-Enterobacter-Serratia group, Citrobacter sp., Proteus sp. (indole-positive and indole-negative), including Proteus mirabilis, P. morganii, P. rettgrei, P. vulgaris, Pseudomonas aeruginosa and Neisseria gonorrhoea. Netilmicin is also active in vitro against isolates of Hemophilus influenzae, Salmonella sp., Shigella sp. and against penicillinase and non-penicillinase-producing Staphylococcus including methicillin-resistant strains. Some strains of Providencia sp., Acinetobacter sp. and Aeromonas sp. are also sensitive to netilmicin. Many strains of the above organisms which are found to be resistant to other aminoglycosides, such as kanamycin, gentamicin, tobramycin and sisomicin, are susceptible to netilmicin in vitro. Occasionally, strains have been identified which are resistant to amikacin but susceptible to netilmicin. The combination of netilmicin and penicillin G has a synergistic bactericidal effect against most strains of Streptococcus faecalis (enterococcus). The combined effect of netilmicin and carbenicillin or ticarcillin is synergistic for many strains of Pseudomonas aeruginosa. In addition, many isolates of Serratia, which are resistant to multiple antibiotics, are inhibited by synergistic combinations of netilmicin with carbenicillin, azlocillin, mezlocillin, cefamandole, cefotaxime or moxalactam. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.
Mechanism of actionAminoglycosides like netilmicin "irreversibly" bind to specific 30S-subunit proteins and 16S rRNA. Specifically netilmicin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes, leaving the bacterium unable to synthesize proteins vital to its growth.
Related Articles
AbsorptionRapidly and completely absorbed after IM administration, peak serum levels were achieved within 30-60 minutes. Aminoglycosides are poorly absorbed orally. Topical absorption is also poor unless severe skin damage is present.
Volume of distributionNot Available
Protein bindingProtein-binding of is low and depends on the test conditions (mainly the concentration of cations in the test medium).
Metabolism

No evidence of metabolic transformation, typically 80% is recoverable in the urine within 24 hours

Route of eliminationNot Available
Half life2.5 hours
ClearanceNot Available
ToxicityNetilmicin has nephrotoxic and ototoxic potential. Nephrotoxicity occurs via drug accumulation in renal proximal tubular cells resulting in cellular damage. Tubular cells may regenerate despite continued exposure and nephrotoxicity is usually mild and reversible. Netilmicin is less nephrotoxic than neomycin, gentamicin, tobramycin, and amikacin, likely due to a reduced number of cationic amino groups in its structure. Otoxicity occurs as a result of irreversible damage to hair cells of the cochlea and/or summit of the ampullar cristae in the vestibular complex caused drug accumulation in the endolymph and perilymph of the inner ear. Otoxicity appears to be correlated to total exposure and may be cumulative with further doses of aminoglycosides or other ototoxic drugs (e.g. cisplatin, furosemide). High frequency hearing loss is followed by low frequency hearing loss, which may be followed by retrograde degeneration of the auditory nerve. Vestibular toxicity may cause vertigo, nausea and vomiting, dizziness and loss of balance.
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
PathwayCategorySMPDB ID
Netilmicin Action PathwayDrug actionSMP00257
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9129
Blood Brain Barrier-0.9912
Caco-2 permeable-0.7057
P-glycoprotein substrateSubstrate0.8191
P-glycoprotein inhibitor IInhibitor0.5133
P-glycoprotein inhibitor IINon-inhibitor0.9479
Renal organic cation transporterNon-inhibitor0.8985
CYP450 2C9 substrateNon-substrate0.8475
CYP450 2D6 substrateNon-substrate0.837
CYP450 3A4 substrateSubstrate0.5494
CYP450 1A2 substrateNon-inhibitor0.8995
CYP450 2C9 inhibitorNon-inhibitor0.9098
CYP450 2D6 inhibitorNon-inhibitor0.9237
CYP450 2C19 inhibitorNon-inhibitor0.9033
CYP450 3A4 inhibitorNon-inhibitor0.9691
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8932
Ames testNon AMES toxic0.7193
CarcinogenicityNon-carcinogens0.9266
BiodegradationNot ready biodegradable0.9944
Rat acute toxicity2.0963 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.981
hERG inhibition (predictor II)Non-inhibitor0.6924
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Schering corp sub schering plough corp
PackagersNot Available
Dosage forms
FormRouteStrength
Solutionintramuscular; intravenous100 mg
Solutionintramuscular; intravenous50 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility100 mg/mLNot Available
logP-3Not Available
Predicted Properties
PropertyValueSource
Water Solubility8.43 mg/mLALOGPS
logP-1.4ALOGPS
logP-3.5ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)12.49ChemAxon
pKa (Strongest Basic)9.97ChemAxon
Physiological Charge5ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area199.73 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity119.84 m3·mol-1ChemAxon
Polarizability50.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Chou-Hong Tann, Tiruvettipuram K. Thiruvengadam, John S. Chiu, Cesar Colon, “Process for preparing netilmicin.” U.S. Patent US4831123, issued June, 1966.

US4831123
General References
  1. Hemsworth S, Nunn AJ, Selwood K, Osborne C, Jones A, Pizer B: Once-daily netilmicin for neutropenic pyrexia in paediatric oncology. Acta Paediatr. 2005 Mar;94(3):268-74. [PubMed:16028643 ]
  2. Klingenberg C, Smabrekke L, Lier T, Flaegstad T: Validation of a simplified netilmicin dosage regimen in infants. Scand J Infect Dis. 2004;36(6-7):474-9. [PubMed:15307571 ]
  3. Brooks JR, Marlow N, Reeves BC, Millar MR: Use of once-daily netilmicin to treat infants with suspected sepsis in a neonatal intensive care unit. Biol Neonate. 2004;86(3):170-5. Epub 2004 Jun 29. [PubMed:15237240 ]
External Links
ATC CodesJ01GB07S01AA23
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSDownload (57 KB)
Interactions
Drug Interactions
Drug
Alendronic acidNetilmicin may increase the activities of Alendronate.
Amphotericin BAmphotericin B may increase the nephrotoxic activities of Netilmicin.
Atracurium besylateNetilmicin may increase the activities of Atracurium besylate.
AvibactamAvibactam may increase the nephrotoxic activities of Netilmicin.
Botulinum Toxin Type ANetilmicin may increase the neuromuscular blocking activities of Botulinum Toxin Type A.
BumetanideThe risk or severity of adverse effects can be increased when Bumetanide is combined with Netilmicin.
CapreomycinCapreomycin may increase the neuromuscular blocking activities of Netilmicin.
CarboplatinNetilmicin may increase the ototoxic activities of Carboplatin.
CefaclorCefaclor may increase the nephrotoxic activities of Netilmicin.
CefdinirCefdinir may increase the nephrotoxic activities of Netilmicin.
CefiximeCefixime may increase the nephrotoxic activities of Netilmicin.
CefotaximeCefotaxime may increase the nephrotoxic activities of Netilmicin.
CefotetanCefotetan may increase the nephrotoxic activities of Netilmicin.
CefoxitinCefoxitin may increase the nephrotoxic activities of Netilmicin.
CefpodoximeCefpodoxime may increase the nephrotoxic activities of Netilmicin.
CefprozilCefprozil may increase the nephrotoxic activities of Netilmicin.
CeftazidimeCeftazidime may increase the nephrotoxic activities of Netilmicin.
CeftibutenCeftibuten may increase the nephrotoxic activities of Netilmicin.
CeftriaxoneCeftriaxone may increase the nephrotoxic activities of Netilmicin.
CefuroximeCefuroxime may increase the nephrotoxic activities of Netilmicin.
CelecoxibCelecoxib may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
Cisatracurium besylateNetilmicin may increase the activities of Cisatracurium besylate.
CisplatinCisplatin may increase the nephrotoxic activities of Netilmicin.
ClavulanateThe serum concentration of Netilmicin can be decreased when it is combined with Clavulanate.
ClodronateNetilmicin may increase the activities of Clodronate.
ColistimethateNetilmicin may increase the nephrotoxic activities of Colistimethate.
ColistinNetilmicin may increase the nephrotoxic activities of Colistin.
CyclosporineNetilmicin may increase the nephrotoxic activities of Cyclosporine.
DiclofenacDiclofenac may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
DiflunisalDiflunisal may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
DigoxinThe serum concentration of Digoxin can be decreased when it is combined with Netilmicin.
Etacrynic acidThe risk or severity of adverse effects can be increased when Ethacrynic acid is combined with Netilmicin.
EtodolacEtodolac may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
FenoprofenFenoprofen may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
FloctafenineFloctafenine may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
FlurbiprofenFlurbiprofen may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
FoscarnetFoscarnet may increase the nephrotoxic activities of Netilmicin.
FurosemideThe risk or severity of adverse effects can be increased when Furosemide is combined with Netilmicin.
IbandronateNetilmicin may increase the activities of Ibandronate.
IbuprofenIbuprofen may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
IndomethacinIndomethacin may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
KetoprofenKetoprofen may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
KetorolacKetorolac may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
MannitolMannitol may increase the nephrotoxic activities of Netilmicin.
MecamylamineNetilmicin may increase the neuromuscular blocking activities of Mecamylamine.
Mefenamic acidMefenamic acid may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
MeloxicamMeloxicam may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
NabumetoneNabumetone may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
NaproxenNaproxen may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
OxaprozinOxaprozin may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
PamidronateNetilmicin may increase the activities of Pamidronate.
PancuroniumNetilmicin may increase the activities of Pancuronium.
PiperacillinThe serum concentration of Netilmicin can be decreased when it is combined with Piperacillin.
PiroxicamPiroxicam may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
RisedronateNetilmicin may increase the activities of Risedronate.
RocuroniumNetilmicin may increase the activities of Rocuronium.
SuccinylcholineNetilmicin may increase the activities of Succinylcholine.
SulindacSulindac may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
TenofovirThe serum concentration of Netilmicin can be increased when it is combined with Tenofovir.
Tiaprofenic acidTiaprofenic acid may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
TicarcillinThe serum concentration of Netilmicin can be decreased when it is combined with Ticarcillin.
TiludronateNetilmicin may increase the activities of Tiludronate.
TolmetinTolmetin may decrease the excretion rate of Netilmicin which could result in a lower serum level and potentially a reduction in efficacy.
TorasemideThe risk or severity of adverse effects can be increased when Torasemide is combined with Netilmicin.
VancomycinVancomycin may increase the nephrotoxic activities of Netilmicin.
VecuroniumNetilmicin may increase the activities of Vecuronium.
Zoledronic acidNetilmicin may increase the activities of Zoledronate.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
yes
Actions
inhibitor
General Function:
Trna binding
Specific Function:
With S4 and S5 plays an important role in translational accuracy.Interacts with and stabilizes bases of the 16S rRNA that are involved in tRNA selection in the A site and with the mRNA backbone. Located at the interface of the 30S and 50S subunits, it traverses the body of the 30S subunit contacting proteins on the other side and probably holding the rRNA structure together. The combined cluste...
Gene Name:
rpsL
Uniprot ID:
P0A7S3
Molecular Weight:
13736.995 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
2. 16S rRNA
Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
yes
Actions
inhibitor
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Tuuminen T, Heinasmaki T, Kerttula T: First report of bacteremia by Asaia bogorensis, in a patient with a history of intravenous-drug abuse. J Clin Microbiol. 2006 Aug;44(8):3048-50. [PubMed:16891542 ]
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12