Langbahn Team – Weltmeisterschaft

Kanamycin A

Not to be confused with Kanamycin B or Keanumycin.

Kanamycin A
Clinical data
Other namesK/KAN/HLK/KM[1]
AHFS/Drugs.comMonograph
Pregnancy
category
  • D
Routes of
administration		By mouth, intravenous, intramuscular
ATC code
Pharmacokinetic data
Bioavailabilityvery low after by mouth delivery
MetabolismUnknown
Elimination half-life2 hours 30 minutes
ExcretionUrine (as unchanged drug)
Identifiers
  • 2-(aminomethyl)- 6-[4,6-diamino-3- [4-amino-3,5-dihydroxy-6-(hydroxymethyl) tetrahydropyran-2-yl]oxy- 2-hydroxy- cyclohexoxy]- tetrahydropyran- 3,4,5-triol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.000.374 Edit this at Wikidata
Chemical and physical data
FormulaC18H36N4O11
Molar mass484.503 g·mol−1
3D model (JSmol)
  • O([C@@H]2[C@@H](O)[C@H](O[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](N)C[C@H]2N)[C@H]3O[C@@H]([C@@H](O)[C@H](N)[C@H]3O)CO
  • InChI=1S/C18H36N4O11/c19-2-6-10(25)12(27)13(28)18(30-6)33-16-5(21)1-4(20)15(14(16)29)32-17-11(26)8(22)9(24)7(3-23)31-17/h4-18,23-29H,1-3,19-22H2/t4-,5+,6-,7-,8+,9-,10-,11-,12+,13-,14-,15+,16-,17-,18-/m1/s1 checkY
  • Key:SBUJHOSQTJFQJX-NOAMYHISSA-N checkY
  (verify)

Kanamycin A,[2] often referred to simply as kanamycin, is an antibiotic used to treat severe bacterial infections and tuberculosis.[3] It is not a first line treatment.[3] It is used by mouth, injection into a vein, or injection into a muscle.[3] Kanamycin is recommended for short-term use only, usually from 7 to 10 days.[3] Since antibiotics only show activity against bacteria, it is ineffective in viral infections.[3]

Common side effects include hearing and balance problems.[3] Kidney problems may also occur.[3] Kanamycin is not recommended during pregnancy as it may harm the baby.[3] It is likely safe during breastfeeding.[4] Kanamycin is in the aminoglycoside family of medications.[3] It has the weakest antibacterial capabilities of all compounds in this family when used clinically, which is partially due to its increased toxicity in comparison to other aminoglycosides.[5] It works by blocking the production of proteins that are required for bacterial survival.[3]

Kanamycin was first isolated in 1957 by Hamao Umezawa from the bacterium Streptomyces kanamyceticus.[3][6] It was removed from the World Health Organization's List of Essential Medicines in 2019.[7][8] It is no longer marketed in the United States.[3]

Medical uses

Spectrum of activity

Kanamycin is indicated for short-term treatment of bacterial infections caused by one or more of the following pathogens: E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, and Acinetobacter species. In cases of serious infection when the causative organism is unknown, Kanamycin injection in conjunction with a penicillin- or cephalosporin-type drug may be given initially before obtaining results of susceptibility testing.[citation needed]

Kanamycin does not treat viral infections.[9]

Pregnancy and breastfeeding

Kanamycin is pregnancy category D in the United States.[9]

Kanamycin enters breast milk in small amounts. The manufacturer therefore advises that people should either stop breastfeeding or kanamycin. The American Academy of Pediatrics considers kanamycin okay in breastfeeding.[10]

Children

Kanamycin should be used with caution in newborns due to the risk of increased drug concentration resulting from immature kidney function.[9]

Side effects

Serious side effects include ringing in the ears or loss of hearing, toxicity to kidneys, and allergic reactions to the drug.[11] Ototoxicity is a common quality among aminoglycosides, and its rate of incidence in kanamycin is around 3-10%.[12]

Other side effects include:[9]

Gastrointestinal effects

  • Nausea, vomiting, diarrhea

Musculoskeletal effects

  • Myasthenia gravis

Neurologic effects

  • Headache
  • Paresthesias
  • Blurring of vision
  • Neuromuscular blockade

Metabolic effects

  • Malabsorption syndrome

Mechanism

Kanamycin works by interfering with protein synthesis. It binds to the 30S subunit of the bacterial ribosome. This results in incorrect alignment with the mRNA and eventually leads to a misread that causes the wrong amino acid to be placed into the peptide. This leads to nonfunctional peptide chains.[13]

Bacterial Resistance

Bacterial resistance to kanamycin is a serious and increasing phenomenon, which is very concerning for its use in treating multidrug-resistant tuberculosis and other multidrug-resistant gram-negative bacterial infections. This is due in part to possible cross-resistance between kanamycin and other aminoglycosides, such as amikacin, capreomycin, and gentamicin.[14] Resistance to these aminoglycosides is due to mutations in the 16S rRNA gene (rrs) within the 30S subunit that stops the antibacterial from binding tightly to the gene.[15] These mutations are most commonly identified through a single-nucleotide variant at the position 1401.[16]

Composition

Kanamycin is a mixture of three main components: kanamycin A, B, and C. Kanamycin A is the major component in kanamycin.[17] The effects of these components do not appear to be widely studied as individual compounds when used against prokaryotic and eukaryotic cells.[citation needed]

Biosynthesis

While the main product produced by Streptomyces kanamyceticus is kanamycin A, additional products are also produced, including kanamycin B, kanamycin C, kanamycin D and kanamycin X.[18]

The kanamycin biosynthetic pathway can be divided into two parts. The first part is common to several aminoglycoside antibiotics, such as butirosin and neomycin. In it a unique aminocyclitol, 2-deoxystreptamine, is biosynthesized from D-glucopyranose 6-phosphate in four steps. At this point the kanamycin pathway splits into two branches due to the promiscuity of the next enzyme, which can utilize two different glycosyl donors - UDP-N-acetyl-α-D-glucosamine and UDP-α-D-glucose. One of the branches forms kanamycin C and kanamycin B, while the other branch forms kanamycin D and kanamycin X. However, both kanamycin B and kanamycin D can be converted to kanamycin A, so both branches of the pathway converge at kanamycin A.[19]

Use in research

Kanamycin is used in molecular biology as a selective agent most commonly to isolate bacteria (e.g., E. coli) which have taken up genes (e.g., of plasmids) coupled to a gene coding for kanamycin resistance (primarily Neomycin phosphotransferase II [NPT II/Neo]). Bacteria that have been transformed with a plasmid containing the kanamycin resistance gene are plated on kanamycin (50-100 μg/mL) containing agar plates or are grown in media containing kanamycin (50-100 μg/mL). Only the bacteria that have successfully taken up the kanamycin resistance gene become resistant and will grow under these conditions. As a powder, kanamycin is white to off-white and is soluble in water (50 mg/mL).[citation needed]

At least one such gene, Atwbc19[20] is native to a plant species, of comparatively large size and its coded protein acts in a manner which decreases the possibility of horizontal gene transfer from the plant to bacteria; it may be incapable of giving resistance to bacteria even if gene transfer occurs.[citation needed]

KanMX marker

The selection marker kanMX is a hybrid gene consisting of a bacterial aminoglycoside phosphotransferase (kanr from transposon Tn903) under control of the strong TEF promoter from Ashbya gossypii.[21][22]

Mammalian cells, yeast, and other eukaryotes acquire resistance to geneticin (= G418, an aminoglycoside antibiotic similar to kanamycin) when transformed with a kanMX marker. In yeast, the kanMX marker avoids the requirement of auxotrophic markers. In addition, the kanMX marker renders E. coli resistant to kanamycin. In shuttle vectors the KanMX cassette is used with an additional bacterial promoter. Several versions of the kanMX cassette are in use, e.g. kanMX1-kanMX6. They primarily differ by additional restriction sites and other small changes around the actual open reading frame.[21][23]

Antibiotic Conjugated Nanoparticle Synthesis

Antibiotic resistance or development of multi-drug resistant bacterial strains is a key challenge for treating bacterial infections. With limited research being carried out to design and develop new antibiotics, novel approaches like functionalizing antibiotic to metal nanoparticles surface to treat resistant bacterial strains have been studied. Kanamycin functionalized gold-nanoparticles (Kan-GNPs) were synthesized and tested for its antibacterial activity against both gram positive and gram negative strains. A dose dependent antibacterial activity was noted for Kan-GNPs in comparison to free kanamycin.[24]

References

  1. ^ "Antibiotic abbreviations list". Retrieved 22 June 2023.
  2. ^ Elks J, Ganellin DR (1990). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 717–. doi:10.1007/BF00171763. S2CID 122125855.
  3. ^ a b c d e f g h i j k l "Kanamycin Sulfate". The American Society of Health-System Pharmacists. Archived from the original on 10 September 2017. Retrieved 6 December 2016.
  4. ^ "Kanamycin (Kantrex) Use During Pregnancy". www.drugs.com. Archived from the original on 20 December 2016. Retrieved 7 December 2016.
  5. ^ Lounis N, Truffot-Pernot C, Grosset J (March 1977). "Which aminoglycoside or fluoroquinolone is more active against Mycobacterium tuberculosis in mice?". Antimicrobial Agents and Chemotherapy. 41 (3): 607–610. doi:10.1128/aac.41.3.607. PMC 163759. PMID 9056001.
  6. ^ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 302. ISBN 9780471899792.
  7. ^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
  8. ^ World Health Organization (2019). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/330668. ISBN 9789241210300. ISSN 0512-3054. WHO technical report series;1021.
  9. ^ a b c d "Kanamycin (By injection)". Archived from the original on 10 September 2017.
  10. ^ Briggs G (2011). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams & Wilkins. p. 787.
  11. ^ Consumer Drug Information: Kanamycin, 2 April 2008, archived from the original on 3 May 2008, retrieved 4 May 2008
  12. ^ Chan ED, Chatterjee D, Iseman MD, Heifets LB (2004). "Pyrazinamide, ethambutol, ethionamide, and aminoglycosides". In Rom WN, Garay SM (ed.). Tuberculosis (2 ed.). Lippincott Williams & Wilkins.
  13. ^ "Kanamycin". DrugBank. 17 August 2016.
  14. ^ Das DJ, Shankar A, Johnson JB, Thomas S (2020). "Critical insights into antibiotic resistance transferability in probiotic Lactobacillus". Nutrition. 69. doi:10.1016/j.nut.2019.110567.
  15. ^ Jugheli L, Bzekalava N, de Rijk P, Fissette K, Portaels F, Rigouts L (2009). "High level of cross-resistance between kanamycin, amikacin, and capreomycin among Mycobacterium tuberculosis isolates from Georgia and a close relation with mutations in the rrs gene". Antimicrobial Agents and Chemotherapy. 53 (12): 5064–5068. doi:10.1128/AAC.00851-09. PMC 2786337. PMID 19752274.
  16. ^ Ley SD, Pillay S, Streicher EM, van der Heijden YF, Sirgel F, Derendinger B, et al. (July 2021). "Melting the eis: Nondetection of Kanamycin Resistance Markers by Routine Diagnostic Tests and Identification of New eis Promoter Variants". Antimicrobial Agents and Chemotherapy. 65 (7). doi:10.1128/AAC.02502-20. PMC 8218670. PMID 33903113.
  17. ^ "Kanamycin". PubChem. U.S. National Library of Medicine.
  18. ^ "Kanamycin Sulfate, USP". TOKU-E. Retrieved 28 June 2024.
  19. ^ "kanamycin biosynthesis pathway". MetaCyc. Retrieved 30 September 2014.
  20. ^ "Horizontal Gene Transfer: Plant vs. Bacterial Genes for Antibiotic Resistance Scenario's—What's the Difference?". Isb.vt.edu. Archived from the original on 6 June 2013. Retrieved 24 June 2013.
  21. ^ a b Wach A, Brachat A, Pöhlmann R, Philippsen P (December 1994). "New heterologous modules for classical or PCR-based gene disruptions in Saccharomyces cerevisiae". Yeast. 10 (13): 1793–1808. doi:10.1002/yea.320101310. PMID 7747518. S2CID 25158247.
  22. ^ Steiner S, Philippsen P (February 1994). "Sequence and promoter analysis of the highly expressed TEF gene of the filamentous fungus Ashbya gossypii". Molecular & General Genetics. 242 (3): 263–271. doi:10.1007/BF00280415. PMID 8107673. S2CID 19928246.
  23. ^ Wach A (March 1996). "PCR-synthesis of marker cassettes with long flanking homology regions for gene disruptions in S. cerevisiae". Yeast. 12 (3): 259–265. doi:10.1002/(SICI)1097-0061(19960315)12:3<259::AID-YEA901>3.0.CO;2-C. PMID 8904338. S2CID 10450123.
  24. ^ Payne JN, Waghwani HK, Connor MG, Hamilton W, Tockstein S, Moolani H, et al. (May 2016). "Novel Synthesis of Kanamycin Conjugated Gold Nanoparticles with Potent Antibacterial Activity". Frontiers in Microbiology. 7: 607. doi:10.3389/fmicb.2016.00607. PMC 4908860. PMID 27330535.
Quelle: http://en.wikipedia.org/wiki/Kanamycin