Identification

Name
Netilmicin
Accession Number
DB00955  (APRD00232)
Type
Small Molecule
Groups
Approved, Investigational
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. 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
  • Netilmycin
Product Ingredients
IngredientUNIICASInChI Key
Netilmicin sulfateS741ZJS97U56391-57-2Not applicable
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Netromycin Inj 100mg/mlSolution100 mgIntramuscular; IntravenousSchering Plough1981-12-312004-07-21Canada
Netromycin Inj 50mg/mlSolution50 mgIntramuscular; IntravenousSchering Plough1981-12-312004-07-21Canada
International/Other Brands
Netromycin
Categories
UNII
4O5J85GJJB
CAS number
56391-56-1
Weight
Average: 475.587
Monoisotopic: 475.30059868
Chemical Formula
C21H41N5O7
InChI Key
CIDUJQMULVCIBT-MQDUPKMGSA-N
InChI
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
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}-5-methyl-4-(methylamino)oxane-3,5-diol
SMILES
CCN[C@@H]1C[C@H](N)[C@@H](O[C@H]2OC(CN)=CC[C@H]2N)[C@H](O)[C@H]1O[C@H]1OC[C@](C)(O)[C@H](NC)[C@H]1O

Pharmacology

Indication

For the treatment of bacteremia, septicaemia, respiratory tract infections, skin and soft-tissue infection, burns, wounds, and peri-operative infections caused by susceptible strains.

Pharmacodynamics

Netilmicin 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 action

Aminoglycosides 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.

TargetActionsOrganism
A30S ribosomal protein S12
inhibitor
Escherichia coli (strain K12)
A16S rRNA
inhibitor
Enteric bacteria and other eubacteria
Absorption

Rapidly 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 distribution
Not Available
Protein binding

Protein-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 elimination
Not Available
Half life

2.5 hours

Clearance
Not Available
Toxicity

Netilmicin 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
PathwayCategory
Netilmicin Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Netilmicin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Netilmicin is combined with (S)-Warfarin.
1,10-PhenanthrolineThe therapeutic efficacy of 1,10-Phenanthroline can be decreased when used in combination with Netilmicin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Netilmicin is combined with 4-hydroxycoumarin.
AbacavirNetilmicin may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseNetilmicin may decrease the excretion rate of Acarbose which could result in a higher serum level.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Aceclofenac is combined with Netilmicin.
AcemetacinThe risk or severity of nephrotoxicity can be increased when Acemetacin is combined with Netilmicin.
AcenocoumarolThe risk or severity of bleeding can be increased when Netilmicin is combined with Acenocoumarol.
AcetaminophenNetilmicin may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Food Interactions
Not 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
Human Metabolome Database
HMDB15090
KEGG Drug
D08268
KEGG Compound
C07657
PubChem Compound
441306
PubChem Substance
46507404
ChemSpider
20152952
ChEBI
7528
ChEMBL
CHEMBL1572
Therapeutic Targets Database
DAP000404
PharmGKB
PA164754913
Wikipedia
Netilmicin
ATC Codes
S01AA23 — NetilmicinJ01GB07 — Netilmicin
MSDS
Download (57 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentOsteomyelitis1
4CompletedTreatmentPneumonia Ventilator Associated1

Pharmacoeconomics

Manufacturers
  • Schering corp sub schering plough corp
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntramuscular; Intravenous100 mg
SolutionIntramuscular; Intravenous50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility100 mg/mLNot Available
logP-3Not Available
Predicted Properties
PropertyValueSource
Water Solubility9.2 mg/mLALOGPS
logP-1.4ALOGPS
logP-3.5ChemAxon
logS-1.7ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)9.8ChemAxon
Physiological Charge5ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area199.73 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity119.84 m3·mol-1ChemAxon
Polarizability50.76 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminocyclitol glycosides. These are organic compounds containing an amicocyclitol moiety glycosidically linked to a carbohydrate moiety. There are two major classes of aminoglycosides containing a 2-streptamine core. They are called 4,5- and 4,6-disubstituted 2-deoxystreptamines.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Aminocyclitol glycosides
Alternative Parents
O-glycosyl compounds / Aminocyclitols and derivatives / Cyclohexylamines / Cyclohexanols / Oxanes / Monosaccharides / Tertiary alcohols / 1,2-aminoalcohols / Oxacyclic compounds / Dialkylamines
show 4 more
Substituents
Amino cyclitol glycoside / Glycosyl compound / O-glycosyl compound / Aminocyclitol or derivatives / Cyclohexanol / Cyclohexylamine / Cyclitol or derivatives / Monosaccharide / Oxane / Cyclic alcohol
show 17 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not 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. Lo...
Gene Name
rpsL
Uniprot ID
P0A7S3
Uniprot Name
30S ribosomal protein S12
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]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:47