Neomycin

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Neomycin
Topical, oral
ATC code
Legal status
Legal status
  • US:
    Neosporin
    and similar ointments
Pharmacokinetic data
BioavailabilityNone
Protein bindingN/A
MetabolismN/A
Elimination half-life2 to 3 hours
Identifiers
  • (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
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=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
 ☒NcheckY (what is this?)  (verify)

Neomycin is an

Gram-positive bacilli and anaerobic Gram-negative bacilli. Neomycin comes in oral and topical formulations, including creams, ointments, and eyedrops. Neomycin belongs to the aminoglycoside class of antibiotics that contain two or more amino sugars connected by glycosidic bonds
.

Neomycin was discovered in 1949 by microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. Neomycin received approval for medical use in 1952.[1] Rutgers University was granted the patent for neomycin in 1957.[2]

Discovery

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.[3] Synthesis requires specific nutrient conditions in either stationary or submerged aerobic conditions. The compound is then isolated and purified from the bacterium.[4]

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. Due to its poor GI tract absorption, orally administered neomycin has also been used to reduce the risk of post operative infection following gastrointestinal surgery.[5]

Waksman and Lechevalier originally noted that neomycin was active against streptomycin-resistant bacteria as well as

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.[7]

In 2022, the combination of neomycin with dexamethasone and polymyxin B was the 274th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[8][9]

Spectrum

Similar to other aminoglycosides, neomycin has excellent activity against

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

Side effects

In 2005–06, Neomycin was the fifth-most-prevalent allergen in

gamma-Aminobutyric acid antagonist and can be responsible for seizures and psychosis.[15] Like other aminoglycosides, neomycin has been shown to be ototoxic, causing tinnitus, hearing loss, and vestibular problems in a small number of patients. Neomycin affects the cochlea, which is found in the inner ear.[16] Hearing loss is caused by ear hair cell death, which occurs in response to treatment with neomycin.[16] 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.[citation needed
]

Molecular biology

Activity

Neomycin's antibacterial activity stems from its binding to the 30S subunit of the prokaryotic ribosome, where it inhibits prokaryotic translation of mRNA.[17]

Neomycin also exhibits a high binding affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of cell membranes.[18]

Resistance

Neomycin resistance is conferred by either one of two

cell lines expressing cloned proteins in culture. Many commercially available protein expression plasmids contain a neo-resistance gene as a selectable marker
. Currently, research is being performed to understand if derivatives of neomycin have the same antibiotic effects while still being effective against neomycin-resistant bacteria.[20]

Biosynthetic pathway

Neomycin was first isolated from the Streptomyces fradiae and Streptomyces albogriseus in 1949 (NBRC 12773).

ototoxic. Its use is thus restricted to the oral treatment of intestinal infections.[22]

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

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).[23] A deacetylase acting to remove the acetyl group on N-acetylglucosamine moieties of aminoglycoside intermediates (Neo16) remains to be clarified (sequence similar to BtrD).[24]

Next is the attachment of the D-ribose via ribosylation of neamine, using 5-phosphoribosyl-1-diphosphate (PRPP) as the ribosyl donor (BtrL, BtrP);[25] glycosyltransferase (potential homologues RibF, LivF, Parf) gene (Neo15).[26]

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.[27]

Neomycin B

Neomycin B and C are 23-carbon molecules with a four-ring structure. Three of the rings are six-membered, and one is five-membered.[28] Neomycin B and Neomycin C are stereoisomers of each other and differ by only one stereocenter one giving the R conformation and the other giving the S conformation.[28] Neomycin C can undergo enzymatic synthesis from ribostamycin.[29]

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.[30] The quantities of these components in neomycin vary from lot-to-lot depending on the manufacturer and manufacturing process.[31]

DNA binding

Aminoglycosides such as neomycin are known for their ability to bind to duplex RNA with high affinity.[32] The association constant for neomycin with A-site RNA is in the 109 M−1 range.[33] 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.[34] 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.[35]

References

  1. ISBN 9783527607495. Archived
    from the original on 2020-08-01. Retrieved 2020-05-25.
  2. ^ US 2799620, Waksman SA, Lechevalier HA, "Neomycin and process of preparation", issued 18 July 1957, assigned to Rutgers Research and Educational Foundation. 
  3. ^ "The Nobel Prize in Physiology or Medicine 1952". Nobel Foundation. Archived from the original on 2018-06-19. Retrieved 2008-10-29.
  4. ^ "Neomycin". Pharmaceutical Manufacturing Encyclopedia. Vol. 3 (3rd ed.). 2007. pp. 2415–2416.
  5. PMID 12067168
    .
  6. ^
    PMID 17782716
    .
  7. S2CID 31248441
    .
  8. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  9. ^ "Dexamethasone; Neomycin; Polymyxin B Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  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. S2CID 24088485
    .
  14. ^ McNamara, Damian. (2010). Neomycin Is Named Contact Allergen of the Year Archived 2015-04-22 at archive.today
  15. S2CID 13551808
    .
  16. ^ a b Langman, A. Neomycin ototoxicity. Otolaryngology Head and Neck Surgery 1994, 110, 441-444.
  17. S2CID 23170091
    .
  18. PMID 2537103
    .
  19. ^ "G418/neomycin-cross resistance?". Archived from the original on 2009-06-25. Retrieved 2008-10-19.
  20. ^ Bera, S.; Zhanel, G.; Schweizer, F. Design, Synthesis, and Antibacterial Activities of Neomycin−Lipid Conjugates: Polycationic Lipids with Potent Gram-Positive Activity | Journal of Medicinal Chemistry. Journal of Medicinal Chemistry 2003, 51, 6160-6164.
  21. PMID 16695766
    .
  22. ISBN 978-0-470-74168-9
    .
  23. PMID 16506694
    .
  24. PMID 21983602
    .
  25. PMID 17482823
    .
  26. S2CID 29942953
    .
  27. PMID 17119636
    .
  28. ^ a b National Center for Biotechnology Information Neomycin. https://pubchem.ncbi.nlm.nih.gov/compound/8378 (accessed Nov 5, 2023).
  29. PMID 19713992
    .
  30. ^ 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.
  31. PMID 4907002
    .
  32. PMID 26811742
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  33. PMID 12056901
    .
  34. PMID 10987412
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  35. PMID 11686727
    .
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