DrugBank: Gentamicin (DB00798)

targets (3) transporters (1)

Identification

Name

Gentamicin

Accession Number

DB00798 (APRD00214)

Type

small molecule

Groups

approved

Description

A complex of three different closely related aminoglycoside sulfates, Gentamicins C1, C2, and C1, obtained from Micromonospora purpurea and related species. They are broad-spectrum antibiotics, but may cause ear and kidney damage. They act to inhibit protein synthesis (genetic translation). [PubChem]

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Not Available

Brand names

Alcomicin
Apogen
Bristagen
G-Mycin
G-Myticin
Garamycin
Garamycin Otic Solution
Genoptic Liquifilm
Genoptic S.O.P.
Gentacidin
Gentafair
Gentak
Gentamar
Gentamcin Sulfate
Jenamicin
Ocu-Mycin
Spectro-Genta
U-gencin

Brand name mixtures

Diprogen Crm (Betamethasone Dipropionate + Gentamicin Sulfate)
Diprogen Ont (Betamethasone Dipropionate + Gentamicin Sulfate)
Garasone Oph/Ot Sol (Betamethasone + Gentamicin Sulfate)
Garasone Ophthalmic Ointment (Betamethasone + Gentamicin Sulfate)
Gentamicin Sulfate in Nacl 0.9% Inj (Gentamicin Sulfate + Sodium Chloride)
Gentocin Durafilm (Betamethasone 21-Acetate + Gentamicin Sulfate)
Gentocin Otic Solution (Betamethasone + Gentamicin Sulfate)
Otomax Ointment (Betamethasone + Clotrimazole + Gentamicin Sulfate)
Sandoz Pentasone (Betamethasone + Gentamicin Sulfate)
Topagen Ont (Betamethasone + Gentamicin Sulfate)
Topagen Spray (Betamethasone + Gentamicin Sulfate)
Valisone G Cream (Betamethasone + Gentamicin Sulfate)
Valisone G Ointment (Betamethasone + Gentamicin Sulfate)

Categories

Anti-Bacterial Agents
Protein Synthesis Inhibitors
Aminoglycosides

CAS number

1403-66-3

Weight

Average: 477.5954
Monoisotopic: 477.316248755

Chemical Formula

C₂₁H₄₃N₅O₇

InChI Key

InChIKey=CEAZRRDELHUEMR-UHFFFAOYSA-N

InChI

InChI=1S/C21H43N5O7/c1-9(25-3)13-6-5-10(22)19(31-13)32-16-11(23)7-12(24)17(14(16)27)33-20-15(28)18(26-4)21(2,29)8-30-20/h9-20,25-29H,5-8,22-24H2,1-4H3

Plain Text

IUPAC Name

2-{[4,6-diamino-3-({3-amino-6-[1-(methylamino)ethyl]oxan-2-yl}oxy)-2-hydroxycyclohexyl]oxy}-5-methyl-4-(methylamino)oxane-3,5-diol

SMILES

CNC(C)C1CCC(N)C(OC2C(N)CC(N)C(OC3OCC(C)(O)C(NC)C3O)C2O)O1

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Aminoglycosides

Substructures

Aminoglycosides
Glycerol and Derivatives
Hydroxy Compounds
Pyrans
Acetals and Derivatives
Aliphatic and Aryl Amines
Ethers
Amino Alcohols
Alcohols and Polyols
Heterocyclic compounds

Pharmacology

Indication

For treatment of serious infections caused by susceptible strains of the following microorganisms: P. aeruginosa, Proteus species (indole-positive and indole-negative), E. coli, Klebsiella-Enterobactor-Serratia species, Citrobacter species and Staphylococcus species (coagulase-positive and coagulase-negative).

Pharmacodynamics

Gentamicin is a broad spectrum aminoglycoside antibiotic. Aminoglycosides work by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA, leaving the bacterium unable to synthesize proteins vital to its growth. Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with penicillin-related antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Mechanism of action

Aminoglycosides like gentamicin "irreversibly" bind to specific 30S-subunit proteins and 16S rRNA. Specifically gentamicin 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.

Absorption

Injections lead to peak serum concentrations in 30-60 minutes. Topical gentamicin is readily absorbed from large burned, denuded, or granulating areas but not through intact skin. Absorption of gentamicin is faster and greater with the cream compared to the ointment. Gentamicin is absorbed in small quantities following topical application to the eye. Gentamicin is also absorbed in small amounts following topical application to the ear (especially if the eardrum is perforated or if tissue damage is present). Gentamicin is very poorly absorbed orally.

Volume of distribution

Not Available

Protein binding

Low (between 0 and 30%)

Metabolism

Route of elimination

Not Available

Half life

3-3½ hours in infants one week to six months of age; this increases to 5½ hours in full-term and large premature infants less than one week old.

Clearance

Not Available

Toxicity

Mild and reversible nephrotoxicity may be observed in 5 - 25% of patients. Gentamicin accumulates in proximal renal tubular cells and causes cell damage. Tubular cell regeneration occurs despite continued drug exposure. Toxicity usually occurs several days following initiation of therapy. May cause irreversible ototoxicity. Otoxocity appears to be correlated to cumulative lifetime exposure. Drug accumulation in the endolymph and perilymph of the inner ear causes irreversible damage to hair cells of the cochlea or summit of ampullar cristae in the vestibular complex. High frequency hearing is lost first with progression leading to loss of low frequency hearing. Further toxicity may lead to retrograde degeneration of the 8th cranial (vestibulocochlear) nerve. Vestibular toxicity may cause vertigo, nausea, vomiting, dizziness and loss of balance. Mouse, intravenous LD50: 52 mg/kg; rat, intravenous LD50: 96 mg/kg.

Affected organisms

Enteric bacteria and other eubacteria

Pathways

Pathway	Name	SMPDB ID
	Gentamicin Pathway	SMP00254

Pharmacoeconomics

Manufacturers

Schering corp sub schering plough corp
Pharmafair inc
Alpharma us pharmaceuticals division
Bausch and lomb pharmaceuticals inc
E fougera div altana inc
Perrigo new york inc
Pharmaderm div altana inc
Taro pharmaceuticals usa inc
King pharmaceuticals inc
Bristol laboratories inc div bristol myers co
International medication systems ltd
Abbott laboratories pharmaceutical products div
App pharmaceuticals llc
Baxter healthcare corp anesthesia and critical care
Hospira inc
Kalapharm inc
Pharmaceutical specialist assoc
Solopak laboratories inc
Teva parenteral medicines inc
Watson laboratories inc
Wyeth ayerst laboratories
B braun medical inc
Baxter healthcare corp
Pharmacia and upjohn co
Novartis pharmaceuticals corp
Akorn inc
Altana inc
Allergan
Alcon universal ltd
Falcon pharmaceuticals ltd
Paco research corp

Packagers

Dosage forms

Form	Route	Strength
Cream	Topical
Liquid	Ophthalmic
Ointment	Ophthalmic
Ointment	Topical
Solution	Auricular (otic)
Solution	Intravenous
Solution	Ophthalmic
Solution / drops	Auricular (otic)
Solution / drops	Ophthalmic

Prices

Unit description	Cost	Unit
Gentak 0.3% Ointment 3.5 gm Tube	19.99 USD	tube
Gentamicin Sulfate 0.1% Cream 15 gm Tube	12.99 USD	tube
Gentamicin Sulfate 0.1% Ointment 15 gm Tube	11.99 USD	tube
Gentamicin Sulfate 0.3% Solution 5ml Bottle	11.99 USD	bottle
Gentamicin sulfate powder	5.05 USD	g
Gentamicin Sulfate 10 mg/ml Solution 2ml Vial	5.0 USD	vial
Gentamicin 40 mg/ml	2.82 USD	ml
Gentamicin ped 10 mg/ml vial	2.4 USD	ml
Gentak 3 mg/ml eye drops	1.91 USD	ml
Gentamicin 3 mg/ml eye drops	1.89 USD	ml
Gentamicin 10 mg/ml vial	1.29 USD	ml
Garamycin 0.3 % Ointment	1.2 USD	g
Sandoz Gentamicin Sulfate 0.3 % Ointment	1.2 USD	g
Garamycin 0.3 % Solution	0.75 USD	ml
Sandoz Gentamicin Sulfate 0.3 % Solution	0.75 USD	ml
Gentamicin 40 mg/ml vial	0.45 USD	ml
Ratio-Gentamicin Sulfate 0.1 % Cream	0.43 USD	g
Ratio-Gentamicin Sulfate 0.1 % Ointment	0.37 USD	g
Gentamicin 0.1% cream	0.16 USD	g
Iso gentamicin 120 mg/100 ml	0.09 USD	ml
Gentamicin 90 mg/ns 100 ml pb	0.05 USD	ml
Isoton gentamicin 40 mg/100 ml	0.05 USD	ml
Gentamicin 60 mg/ns 100 ml pb	0.04 USD	ml
Gentamicin 100 mg/ns 100 ml	0.03 USD	ml
Gentamicin 80 mg/ns 100 ml pb	0.03 USD	ml

Patents

Not Available

Properties

State

solid

Melting point

105°C (218-237°C as sulfate salt)

Experimental Properties

Property	Value	Source
water solubility	100 mg/mL	PhysProp
logP	-3.1	PhysProp

Predicted Properties

Property	Value	Source
water solubility	1.26e+01 g/l	ALOGPS
logP	-1.64	ALOGPS
logP	-3.14	ChemAxon Molconvert
logS	-1.58	ALOGPS
pKa	13.16	ChemAxon Molconvert
hydrogen acceptor count	12	ChemAxon Molconvert
hydrogen donor count	8	ChemAxon Molconvert
polar surface area	199.73	ChemAxon Molconvert
rotatable bond count	7	ChemAxon Molconvert
refractivity	118.02	ChemAxon Molconvert
polarizability	51.92	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Compound	C00505
PubChem Compound	3467
PubChem Substance	46506523
ChemSpider	3348
ChEBI	17833
ChEMBL	17833
Therapeutic Targets Database	DAP000116
PharmGKB	PA449753
Drug Product Database	776521
RxList	http://www.rxlist.com/cgi/generic2/pedgenta.htm
Drugs.com	http://www.drugs.com/cdi/gentamicin-drops.html
PDRhealth	http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/gar1187.shtml
Wikipedia	http://en.wikipedia.org/wiki/Gentamicin

ATC Codes

D06AX07
J01GB03
S01AA11
S02AA14
S03AA06

AHFS Codes

84:04.04
08:12.02
52:04.04

PDB Entries

1P87

FDA label

Not Available

MSDS

show (59.2 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. 30S ribosomal protein S12 Pharmacological action: yes Actions: adduct Cryo-EM studies suggest that S12 contacts the EF-Tu bound tRNA in the A-site during codon-recognition. This contact is most likely broken as the aminoacyl-tRNA moves into the peptidyl transferase center in the 50S subunit Organism class: bacterial UniProt ID: P0A7S3 Gene: rpsL Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed 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 Gill AE, Amyes SG: The contribution of a novel ribosomal S12 mutation to aminoglycoside resistance of Escherichia coli mutants. J Chemother. 2004 Aug;16(4):347-9. Pubmed Tamehiro N, Hosaka T, Xu J, Hu H, Otake N, Ochi K: Innovative approach for improvement of an antibiotic-overproducing industrial strain of Streptomyces albus. Appl Environ Microbiol. 2003 Nov;69(11):6412-7. Pubmed Hu H, Ochi K: Novel approach for improving the productivity of antibiotic-producing strains by inducing combined resistant mutations. Appl Environ Microbiol. 2001 Apr;67(4):1885-92. Pubmed Schroeder R, Waldsich C, Wank H: Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 2000 Jan 4;19(1):1-9. Pubmed 2. 16S rRNA Pharmacological action: yes Actions: adduct In prokaryotes, the 16S rRNA is essential for recognizing the 5' end of mRNA and hence positioning it correctly on the ribosome. The 16S rRNA has a characteristic secondary structure in which half of the nucleotides are base-paired. The 16S rRNA sequence has been highly conserved and is often used for evolutionary and species comparative analysis. Gene Sequence: FASTA References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed 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 Doi Y, de Oliveira Garcia D, Adams J, Paterson DL: Coproduction of novel 16S rRNA methylase RmtD and metallo-beta-lactamase SPM-1 in a panresistant Pseudomonas aeruginosa isolate from Brazil. Antimicrob Agents Chemother. 2007 Mar;51(3):852-6. Epub 2006 Dec 11. Pubmed Bogaerts P, Galimand M, Bauraing C, Deplano A, Vanhoof R, De Mendonca R, Rodriguez-Villalobos H, Struelens M, Glupczynski Y: Emergence of ArmA and RmtB aminoglycoside resistance 16S rRNA methylases in Belgium. J Antimicrob Chemother. 2007 Mar;59(3):459-64. Epub 2007 Jan 15. Pubmed Aslangul E, Massias L, Meulemans A, Chau F, Andremont A, Courvalin P, Fantin B, Ruimy R: Acquired gentamicin resistance by permeability impairment in Enterococcus faecalis. Antimicrob Agents Chemother. 2006 Nov;50(11):3615-21. Pubmed Schroeder R, Waldsich C, Wank H: Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 2000 Jan 4;19(1):1-9. Pubmed 3. Low-density lipoprotein receptor-related protein 2 Pharmacological action: no Actions: other/unknown May participate in regulation of parathyroid-hormone and para-thyroid-hormone-related protein release Organism class: human UniProt ID: P98164 Gene: LRP2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Watanabe A, Nagai J, Adachi Y, Katsube T, Kitahara Y, Murakami T, Takano M: Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists. J Control Release. 2004 Mar 24;95(3):423-33. Pubmed Takamoto K, Kawada M, Ikeda D, Yoshida M: Apolipoprotein E3 (apoE3) safeguards pig proximal tubular LLC-PK1 cells against reduction in SGLT1 activity induced by gentamicin C. Biochim Biophys Acta. 2005 Apr 15;1722(3):247-53. Pubmed Nagai J, Saito M, Adachi Y, Yumoto R, Takano M: Inhibition of gentamicin binding to rat renal brush-border membrane by megalin ligands and basic peptides. J Control Release. 2006 May 1;112(1):43-50. Epub 2006 Feb 20. Pubmed

Targets

1. 30S ribosomal protein S12

Pharmacological action: yes
Actions: adduct

Cryo-EM studies suggest that S12 contacts the EF-Tu bound tRNA in the A-site during codon-recognition. This contact is most likely broken as the aminoacyl-tRNA moves into the peptidyl transferase center in the 50S subunit

Organism class: bacterial
UniProt ID: P0A7S3 Link_out

Gene: rpsL
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
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
Gill AE, Amyes SG: The contribution of a novel ribosomal S12 mutation to aminoglycoside resistance of Escherichia coli mutants. J Chemother. 2004 Aug;16(4):347-9. Pubmed
Tamehiro N, Hosaka T, Xu J, Hu H, Otake N, Ochi K: Innovative approach for improvement of an antibiotic-overproducing industrial strain of Streptomyces albus. Appl Environ Microbiol. 2003 Nov;69(11):6412-7. Pubmed
Hu H, Ochi K: Novel approach for improving the productivity of antibiotic-producing strains by inducing combined resistant mutations. Appl Environ Microbiol. 2001 Apr;67(4):1885-92. Pubmed
Schroeder R, Waldsich C, Wank H: Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 2000 Jan 4;19(1):1-9. Pubmed

2. 16S rRNA

Pharmacological action: yes
Actions: adduct

In prokaryotes, the 16S rRNA is essential for recognizing the 5' end of mRNA and hence positioning it correctly on the ribosome. The 16S rRNA has a characteristic secondary structure in which half of the nucleotides are base-paired. The 16S rRNA sequence has been highly conserved and is often used for evolutionary and species comparative analysis.

Gene Sequence: FASTA

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
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
Doi Y, de Oliveira Garcia D, Adams J, Paterson DL: Coproduction of novel 16S rRNA methylase RmtD and metallo-beta-lactamase SPM-1 in a panresistant Pseudomonas aeruginosa isolate from Brazil. Antimicrob Agents Chemother. 2007 Mar;51(3):852-6. Epub 2006 Dec 11. Pubmed
Bogaerts P, Galimand M, Bauraing C, Deplano A, Vanhoof R, De Mendonca R, Rodriguez-Villalobos H, Struelens M, Glupczynski Y: Emergence of ArmA and RmtB aminoglycoside resistance 16S rRNA methylases in Belgium. J Antimicrob Chemother. 2007 Mar;59(3):459-64. Epub 2007 Jan 15. Pubmed
Aslangul E, Massias L, Meulemans A, Chau F, Andremont A, Courvalin P, Fantin B, Ruimy R: Acquired gentamicin resistance by permeability impairment in Enterococcus faecalis. Antimicrob Agents Chemother. 2006 Nov;50(11):3615-21. Pubmed
Schroeder R, Waldsich C, Wank H: Modulation of RNA function by aminoglycoside antibiotics. EMBO J. 2000 Jan 4;19(1):1-9. Pubmed

3. Low-density lipoprotein receptor-related protein 2

Pharmacological action: no
Actions: other/unknown

May participate in regulation of parathyroid-hormone and para-thyroid-hormone-related protein release

Organism class: human
UniProt ID: P98164 Link_out

Gene: LRP2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Watanabe A, Nagai J, Adachi Y, Katsube T, Kitahara Y, Murakami T, Takano M: Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists. J Control Release. 2004 Mar 24;95(3):423-33. Pubmed
Takamoto K, Kawada M, Ikeda D, Yoshida M: Apolipoprotein E3 (apoE3) safeguards pig proximal tubular LLC-PK1 cells against reduction in SGLT1 activity induced by gentamicin C. Biochim Biophys Acta. 2005 Apr 15;1722(3):247-53. Pubmed
Nagai J, Saito M, Adachi Y, Yumoto R, Takano M: Inhibition of gentamicin binding to rat renal brush-border membrane by megalin ligands and basic peptides. J Control Release. 2006 May 1;112(1):43-50. Epub 2006 Feb 20. Pubmed

Transporters
1. Solute carrier family 22 member 6 Actions: inhibitor UniProt ID: Q4U2R8 Gene: hROAT1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, Endou H: The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther. 1999 Aug;290(2):672-7. Pubmed

Transporters

1. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out

Gene: hROAT1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, Endou H: The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther. 1999 Aug;290(2):672-7. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:43

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.