DT-Web

DB00479 - Amikacin


Identification
Name Amikacin
Accession Number DB00479 (APRD00550)
Type small molecule
Description Amikacin is a semi-synthetic aminoglycoside antibiotic derived from kanamycin A. Similar to other aminoglycosides, amikacin disrupts bacterial protein synthesis by binding to the 30S ribosome of susceptible organisms. Binding interferes with mRNA binding and tRNA acceptor sites leading to the production of non-functional or toxic peptides. Other mechanisms not fully understood may confer the bactericidal effects of amikacin. Amikacin is also nephrotoxic and ototoxic.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 585.6025
Groups approved
Monoisotopic Weight 585.285736487
Pharmacology
Indication For short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (Mima-Herellea) species. Amikacin may also be used to treat Mycobacterium avium and Mycobacterium tuberculosis infections.
Mechanism of action Aminoglycosides like Amikacin "irreversibly" bind to specific 30S-subunit proteins and 16S rRNA. Amikacin inhibits protein synthesis by binding to the 30S ribosomal subunit to prevent the formation of an initiation complex with messenger RNA. Specifically Amikacin 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 Rapidly absorbed after intramuscular administration. Rapid absorption occurs from the peritoneum and pleura. Poor oral and topical absorption. Poorly absorbed from bladder irrigations and intrathecal administration.
Protein binding 0-11%
Biotransformation Not Available
Route of elimination Amikacin is excreted primarily by glomerular filtration.
Toxicity Mild and reversible nephrotoxicity may be observed in 5 - 25% of patients. Amikacin accumulates in proximal renal tubular cells. 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.
Affected organisms
  • Enteric bacteria and other eubacteria
Interactions
Drug Interactions
Drug Mechanism of interaction
Atracurium The agent increases the effect of muscle relaxant
Bumetanide Increased ototoxicity
Cefalotin Increased risk of nephrotoxicity
Cefamandole Increased risk of nephrotoxicity
Cefazolin Increased risk of nephrotoxicity
Cefonicid Increased risk of nephrotoxicity
Cefoperazone Increased risk of nephrotoxicity
Ceforanide Increased risk of nephrotoxicity
Cefotaxime Increased risk of nephrotoxicity
Cefotetan Increased risk of nephrotoxicity
Cefoxitin Increased risk of nephrotoxicity
Cefradine Increased risk of nephrotoxicity
Ceftazidime Increased risk of nephrotoxicity
Ceftizoxime Increased risk of nephrotoxicity
Ceftriaxone Increased risk of nephrotoxicity
Cefuroxime Increased risk of nephrotoxicity
Cephapirin Increased risk of nephrotoxicity
Cisplatin Increased risk of nephrotoxicity
Colistimethate Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Due to the potential for additive or synergistic toxicities (including both nephrotoxicity and neuromuscular blockade) between colistimethate and the aminoglycoside antibiotics, this combination should be avoided whenever possible. If these agents must be used together, patients' renal and neuromuscular function should be monitored closely.
Doxacurium chloride The agent increases the effect of muscle relaxant
Ethacrynic acid Increased ototoxicity
Furosemide Increased ototoxicity
Metocurine The agent increases the effect of muscle relaxant
Mivacurium The agent increases the effect of muscle relaxant
Pancuronium The agent increases the effect of muscle relaxant
Pipecuronium The agent increases the effect of muscle relaxant
Rocuronium The agent increases the effect of muscle relaxant
Succinylcholine The agent increases the effect of muscle relaxant
Tacrolimus Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Amikacin. Use caution during concomitant therapy.
Thalidomide Thalidomide increases the renal toxicity of the aminoglycoside
Ticarcillin Ticarcillin may reduce the serum concentration of Amikacin. Ticarcillin may inactivate Amikacin in vitro and the two agents should not be administered simultaneously through the same IV line.
Torasemide Increased ototoxicity
Tubocurarine The agent increases the effect of muscle relaxant
Vecuronium The agent increases the effect of muscle relaxant
Food Interactions Not Available

Targets


30S ribosomal protein S12
Name 30S ribosomal protein S12
Gene Name rpsL
Pharmacological action yes
Actions inhibitor
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
  • Tolmasky ME: Bacterial resistance to aminoglycosides and beta-lactams: the Tn1331 transposon paradigm. Front Biosci. 2000 Jan 1;5:D20-9. - Pubmed
DTHybrid score 1.0615
16S rRNA
Name 16S rRNA
Gene Name Not Available
Pharmacological action unknown
Actions inhibitor
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
  • Possoz C, Newmark J, Sorto N, Sherratt DJ, Tolmasky ME: Sublethal concentrations of the aminoglycoside amikacin interfere with cell division without affecting chromosome dynamics. Antimicrob Agents Chemother. 2007 Jan;51(1):252-6. Epub 2006 Oct 16. - Pubmed
DTHybrid score Not Available

Predictions


Id Partner name Gene Name Score
6704 30S ribosomal protein S12 rpsL 1.0615
4388 Aminoglycoside 2'-N-acetyltransferase aac 0.1234
1162 C-X-C chemokine receptor type 4 CXCR4 0.0691
1244 Low-density lipoprotein receptor-related protein 2 LRP2 0.0525
6028 Kanamycin nucleotidyltransferase knt 0.0448
3390 Aminoglycoside 3'-phosphotransferase aphA 0.0448
6029 Aminoglycoside 3'-phosphotransferase aphA1 0.0448
4240 Protein disulfide-isomerase P4HB 0.0444
1729 Solute carrier family 22 member 6 SLC22A6 0.044
4565 Aminoglycoside 6'-N-acetyltransferase aac(6')-Iy 0.0363
6208 30S ribosomal protein S13 rpsM 0.0281
6706 30S ribosomal protein S13 rpsM 0.0281
6209 30S ribosomal protein S19 rpsS 0.0245
6712 30S ribosomal protein S19 rpsS 0.0245
6726 30S ribosomal protein S19 rpsS 0.0245
6207 30S ribosomal protein S14 rpsN 0.0245
140 30S ribosomal protein S9 rpsI 0.0185
6719 30S ribosomal protein S9 rpsI 0.0185
6725 30S ribosomal protein S9 rpsI 0.0185
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