Neomycin

Neomycin
Names
Trade namesNeo-rx, others
Other namesNeomycin sulfate
IUPAC name
  • (2RS,3S,4S,5R)-5-Amino-2-(aminomethyl)-6-((2R,3S,4R,5S)-5-((1R,2R,5R,6R)-3,5-diamino-2-((2R,3S,4R,5S)-3-amino-6-(aminomethyl)-4,5-dihydroxytetrahydro-2H-pyran-2-yloxy)-6-hydroxycyclohexyloxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yloxy)tetrahydro-2H-pyran-3,4-diol
Clinical data
Drug classAminoglycoside[1]
Main usesApplied to skin: Superficial bacterial skin infections[1]
By mouth: Hepatic encephalopathy, bowel preparation[2][3]
Eye and ear: Conjunctivitis , otitis externa[4]
Side effectsApplied to skin: Contact dermatitis[1]
By mouth: Nausea, diarrhea, abdominal pain[3]
Pregnancy
category
  • US: C/D
    Routes of
    use    		Topical, by mouth
    External links
    AHFS/Drugs.comSystemic: Monograph
    Topical: Monograph
    Eye and ear: Monograph
    MedlinePlusa682274
    Legal
    Legal status
    Pharmacokinetics
    BioavailabilityNone
    Protein bindingN/A
    MetabolismN/A
    Elimination half-life2 to 3 hours
    Chemical and physical data
    FormulaC23H46N6O13
    Molar mass614.650 g·mol−1
    3D model (JSmol)
    SMILES
    • O([C@H]3[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@H]1O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]1N)[C@H]2O)[C@@H](O)[C@H](N)C[C@@H]3N)[C@H]4O[C@@H]([C@@H](O)[C@H](O)[C@H]4N)CN
    InChI
    • InChI=1S/C23H46N6O13/c24-2-7-13(32)15(34)10(28)21(37-7)40-18-6(27)1-5(26)12(31)20(18)42-23-17(36)19(9(4-30)39-23)41-22-11(29)16(35)14(33)8(3-25)38-22/h5-23,30-36H,1-4,24-29H2/t5-,6+,7+,8?,9+,10+,11-,12+,13+,14-,15+,16-,17+,18-,19+,20-,21+,22-,23-/m0/s1 ☒N
    • Key:PGBHMTALBVVCIT-DPNHOFNISA-N ☒N

    Neomycin is an antibiotic.[1] Applied to the skin it is used to treat superficial bacterial skin infections.[1] By mouth it is used to sterilize the bowel before surgery and to treat hepatic encephalopathy.[2][3] As an eye drop it is used for conjunctivitis and as an ear drop it is used for otitis externa.[4]

    Common side affects when applied to the skin include contact dermatitis.[1] Common side effects when taken by mouth include nausea, diarrhea, and abdominal pain.[3] Other side effects when taken by mouth may include hearing problems, balance problems, kidney problems, and seizures.[3] While it is unclear if applying it to the skin is safe in pregnancy, taking it by mouth may harm the baby.[1][3] It is in the aminoglycoside class.[1]

    Neomycin was discovered in 1949 and approval for medical use in 1952.[5][6] It is available as a generic medication.[2] The cream is available in combination with polymyxin B, bacitracin, or hydrocortisone and over the counter.[1] In the United States 100 tablets of 500 mg cost about 86 USD as of 2021.[7] In the United Kingdom combination products applied externally are generally inexpensive.[2]

    Medical uses

    Neomycin is typically applied as a topical preparation, such as Neosporin (neomycin/polymyxin B/bacitracin). The antibiotic can also be administered orally, in which case it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract and has been used as a preventive measure for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, Neomycin keeps ammonia levels low and prevents hepatic encephalopathy, especially before gastrointestinal surgery.

    It is active against streptomycin-resistant bacteria as well as Mycobacterium tuberculosis, the causative agent for tuberculosis.[8] Neomycin has also been used to treat small intestinal bacterial overgrowth. Neomycin is not administered via injection, as it is extremely nephrotoxic (damaging to kidney function) even when compared to other aminoglycosides. The exception is when neomycin is included, in small quantities, as a preservative in some vaccines – typically 25 μg per dose.[9]

    Spectrum

    Similar to other aminoglycosides, neomycin has excellent activity against gram-negative bacteria and is partially effective against gram-positive bacteria. It is relatively toxic to humans, with allergic reactions noted as a common adverse reaction (see: hypersensitivity).[10] Physicians sometimes recommend using antibiotic ointments without neomycin, such as Polysporin.[11] The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant gram-negative bacteria.[12]

    • Enterobacter cloacae: >16 μg/ml
    • Escherichia coli: 1 μg/ml
    • Proteus vulgaris: 0.25 μg/ml

    Dosage

    For hepatic ecephalopathy it is take as 1 gram every 6 hours for 5 to 7 days.[2]

    Side effects

    In 2005–06, Neomycin was the fifth-most-prevalent allergen in patch test results (10.0%).[13] It is also a known GABA gamma-Aminobutyric acid antagonist and can be responsible for seizures and psychosis.[14] Like other aminoglycosides, neomycin has been shown to be ototoxic, causing tinnitus, hearing loss, and vestibular problems in a small number of patients. Patients with existing tinnitus or sensorineural hearing loss are advised to speak with a healthcare practitioner about the risks and side effects prior to taking this medication.

    Pharmacology

    Molecular biology

    Neomycin resistance is conferred by either one of two kanamycin kinase genes.[15] Genes conferring neomycin-resistance are commonly included in DNA plasmids used to establish stable mammalian cell lines expressing cloned proteins in culture. Many commercially available protein expression plasmids contain a neo-resistance gene as a selectable marker.

    Neomycin's antibacterial activity stems from its binding to the 30S subunit of the prokaryotic ribosome, where it inhibits prokaryotic translation of mRNA.[16]

    Neomycin also exhibits a high binding affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of cell membranes.[17]

    Biosynthetic pathway

    Neomycin was first isolated from the Streptomyces fradiae and Streptomyces albogriseus in 1949 (NBRC 12773).[18] Neomycin is a mixture of neomycin B (framycetin); and its epimer neomycin C, the latter component accounting for some 5–15% of the mixture. It is a basic compound that is most active with an alkaline reaction.[8] It is also thermostable and soluble in water (while insoluble in organic solvents).[8] Neomycin has good activity against gram-positive and gram-negative bacteria, but is ototoxic. Its use is thus restricted to the oral treatment of intestinal infections.[19]

    Neomycin B is composed of four linked moieties: D-neosamine, 2-deoxystreptamine (2-DOS), D-ribose, and L-neosamine.

    Neomycin A, also called neamine, contains D-neosamine and 2-deoxystreptamine. Six genes are responsible for neamine biosynthesis: DOIS gene (btrC, neo7); L-glutamine:DOI aminotransferase gene (btrS, neo6); a putative glycosyltransferase gene (btrM, neo8); a putative aminotransferase (similar to glutamate-1-semialdehyde 2,1-aminomutase) gene (btrB, neo18); a putative alcohol dehydrogenase gene (btrE, neo5); and another putative dehydrogenase (similar to chorine dehydrogenase and related flavoproteins) gene (btrQ, neo11).[20] A deacetylase acting to remove the acetyl group on N-acetylglucosamine moieties of aminoglycoside intermediates (Neo16) remains to be clarified (sequence similar to BtrD).[21]

    Next is the attachment of the D-ribose via ribosylation of neamine, using 5-phosphoribosyl-1-diphosphate (PRPP) as the ribosyl donor (BtrL, BtrP);[22] glycosyltransferase (potential homologues RibF, LivF, Parf) gene (Neo15).[23]

    Neosamine B (L-neosamine B) is most likely biosynthesized in the same manner as the neosamine C (D-niosamine) in neamine biosynthesis, but with an additional epimerization step required to account for the presence of the epimeric neosamine B in neomycin B.[24]

    Neomycin B

    Neomycin C can undergo enzymatic synthesis from ribostamycin.[25]

    Composition

    Standard grade neomycin is composed of several related compounds including neomycin A (neamine), neomycin B (framycetin), neomycin C, and a few minor compounds found in much lower quantities. Neomycin B is the most active component in neomycin followed by neomycin C and neomycin A. Neomycin A is an inactive degradation product of the C and B isomers.[26] The quantities of these components in neomycin vary from lot-to-lot depending on the manufacturer and manufacturing process.[27]

    DNA binding

    Aminoglycosides such as neomycin are known for their ability to bind to duplex RNA with high affinity.[28] The association constant for neomycin with A-site RNA is in the 109 M−1 range.[29] However, more than 50 years after its discovery, its DNA-binding properties were still unknown. Neomycin has been shown to induce thermal stabilization of triplex DNA, while having little or almost no effect on the B-DNA duplex stabilization.[30] Neomycin was also shown to bind to structures that adopt an A-form structure, triplex DNA being one of them. Neomycin also includes DNA:RNA hybrid triplex formation.[31]

    History

    Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. It is produced naturally by the bacterium Streptomyces fradiae.[32] Synthesis requires specific nutrient conditions in either stationary or submerged aerobic conditions. The compound is then isolated and purified from the bacterium.[33] Rutgers University was granted the patent for neomycin in 1957.[34]

    References

    1. 1 2 3 4 5 6 7 8 9 "Neomycin (Topical) Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 12 November 2021.
    2. 1 2 3 4 5 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 547. ISBN 978-0857114105.
    3. 1 2 3 4 5 6 "Neomycin (Systemic) Monograph for Professionals". Drugs.com. Archived from the original on 29 April 2021. Retrieved 13 November 2021.
    4. 1 2 "Neomycin (EENT) Monograph for Professionals". Drugs.com. Archived from the original on 28 January 2021. Retrieved 13 November 2021.
    5. ↑ Ricci, Alfredo (25 June 2008). Amino Group Chemistry: From Synthesis to the Life Sciences. John Wiley & Sons. p. 306. ISBN 978-3-527-62127-9. Archived from the original on 13 November 2021. Retrieved 13 November 2021.
    6. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 507. ISBN 9783527607495. Archived from the original on 2020-08-01. Retrieved 2020-05-25.
    7. ↑ "Neomycin Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 29 April 2021. Retrieved 13 November 2021.
    8. 1 2 3 Waksman SA, Lechevalier HA (March 1949). "Neomycin, a New Antibiotic Active against Streptomycin-Resistant Bacteria, including Tuberculosis Organisms". Science. New York, N.Y. 109 (2830): 305–7. Bibcode:1949Sci...109..305W. doi:10.1126/science.109.2830.305. PMID 17782716.
    9. ↑ Heidary N, Cohen DE (September 2005). "Hypersensitivity reactions to vaccine components". Dermatitis. 16 (3): 115–20. doi:10.1097/01206501-200509000-00004. PMID 16242081.
    10. ↑ DermNet dermatitis/neomycin-allergy
    11. ↑ "Your Medicine Cabinet". DERMAdoctor.com, Inc. Archived from the original on 2009-07-09. Retrieved 2008-10-19.
    12. ↑ "Neomycin sulfate, EP Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). TOKU-E. Archived (PDF) from the original on 2015-12-22. Retrieved 2014-03-31.
    13. ↑ Zug KA, Warshaw EM, Fowler JF, Maibach HI, Belsito DL, Pratt MD, et al. (2009). "Patch-test results of the North American Contact Dermatitis Group 2005-2006". Dermatitis. 20 (3): 149–60. doi:10.2310/6620.2009.08097. PMID 19470301.
    14. ↑ Lee C, de Silva AJ. Interaction of neuromuscular blocking effects of neomycin and polymyxin B. Anesthesiology. 1979;50(3):218–220. doi:10.1097/00000542-197903000-00010
    15. ↑ "G418/neomycin-cross resistance?". Archived from the original on 2009-06-25. Retrieved 2008-10-19.
    16. ↑ Mehta R, Champney WS (September 2003). "Neomycin and paromomycin inhibit 30S ribosomal subunit assembly in Staphylococcus aureus". Current Microbiology. 47 (3): 237–43. doi:10.1007/s00284-002-3945-9. PMID 14570276.
    17. ↑ Gabev E, Kasianowicz J, Abbott T, McLaughlin S (February 1989). "Binding of neomycin to phosphatidylinositol 4,5-bisphosphate (PIP2)". Biochimica et Biophysica Acta (BBA) - Biomembranes. 979 (1): 105–12. doi:10.1016/0005-2736(89)90529-4. PMID 2537103.
    18. ↑ Waksman SA, Lechevalier HA, Harris DA (September 1949). "Neomycin—Production and Antibiotic Properties 123". The Journal of Clinical Investigation. 28 (5 Pt 1): 934–9. doi:10.1172/JCI102182. PMC 438928. PMID 16695766.
    19. ↑ Dewick M D (March 2009). Medicinal natural products: a biosynthetic approach (3rd ed.). The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom: John Wiley and Sons Ltd. pp. 508, 510, 511. ISBN 978-0-470-74168-9.{{cite book}}: CS1 maint: location (link)
    20. ↑ Kudo F, Yamamoto Y, Yokoyama K, Eguchi T, Kakinuma K (December 2005). "Biosynthesis of 2-deoxystreptamine by three crucial enzymes in Streptomyces fradiae NBRC 12773". The Journal of Antibiotics. 58 (12): 766–74. doi:10.1038/ja.2005.104. PMID 16506694.
    21. ↑ Park JW, Park SR, Nepal KK, Han AR, Ban YH, Yoo YJ, et al. (October 2011). "Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation". Nature Chemical Biology. 7 (11): 843–52. doi:10.1038/nchembio.671. PMID 21983602.
    22. ↑ Kudo F, Fujii T, Kinoshita S, Eguchi T (July 2007). "Unique O-ribosylation in the biosynthesis of butirosin". Bioorganic & Medicinal Chemistry. 15 (13): 4360–8. doi:10.1016/j.bmc.2007.04.040. PMID 17482823.
    23. ↑ Fan Q, Huang F, Leadlay PF, Spencer JB (September 2008). "The neomycin biosynthetic gene cluster of Streptomyces fradiae NCIMB 8233: genetic and biochemical evidence for the roles of two glycosyltransferases and a deacetylase". Organic & Biomolecular Chemistry. 6 (18): 3306–14. doi:10.1039/B808734B. PMID 18802637. Archived from the original on 2021-03-18. Retrieved 2019-12-25.
    24. ↑ Llewellyn NM, Spencer JB (December 2006). "Biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics". Natural Product Reports. 23 (6): 864–74. doi:10.1039/B604709M. PMID 17119636.
    25. ↑ Kudo F, Kawashima T, Yokoyama K, Eguchi T (November 2009). "Enzymatic preparation of neomycin C from ribostamycin". The Journal of Antibiotics. 62 (11): 643–6. doi:10.1038/ja.2009.88. PMID 19713992.
    26. ↑ Cammack R, Attwood TK, Campbell PN, Parish JH, Smith AD, Stirling JL, Vella F (2006). "neomycin". Oxford Dictionary of Biochemistry and Molecular Biology (2nd ed.). Oxford University Press. p. 453.
    27. ↑ Tsuji K, Robertson JH, Baas R, McInnis DJ (September 1969). "Comparative study of responses to neomycins B and C by microbiological and gas-liquid chromatographic assay methods". Applied Microbiology. 18 (3): 396–8. doi:10.1128/AEM.18.3.396-398.1969. PMC 377991. PMID 4907002.
    28. ↑ Jin Y, Watkins D, Degtyareva NN, Green KD, Spano MN, Garneau-Tsodikova S, Arya DP (January 2016). "Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity". MedChemComm. 7 (1): 164–169. doi:10.1039/C5MD00427F. PMC 4722958. PMID 26811742.
    29. ↑ Kaul M, Pilch DS (June 2002). "Thermodynamics of aminoglycoside-rRNA recognition: the binding of neomycin-class aminoglycosides to the A site of 16S rRNA". Biochemistry. 41 (24): 7695–706. doi:10.1021/bi020130f. PMID 12056901.
    30. ↑ Arya DP, Coffee RL (September 2000). "DNA triple helix stabilization by aminoglycoside antibiotics". Bioorganic & Medicinal Chemistry Letters. 10 (17): 1897–9. doi:10.1016/S0960-894X(00)00372-3. PMID 10987412.
    31. ↑ Arya DP, Coffee RL, Charles I (November 2001). "Neomycin-induced hybrid triplex formation". Journal of the American Chemical Society. 123 (44): 11093–4. doi:10.1021/ja016481j. PMID 11686727.
    32. ↑ "The Nobel Prize in Physiology or Medicine 1952". Nobel Foundation. Archived from the original on 2018-06-19. Retrieved 2008-10-29.
    33. ↑ "Neomycin". Pharmaceutical Manufacturing Encyclopedia. Vol. 3 (3rd ed.). 2007. pp. 2415–2416.
    34. ↑ "Archived copy". Archived from the original on 2021-01-27. Retrieved 2021-02-15.{{cite web}}: CS1 maint: archived copy as title (link)
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