Neomycin

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Neomycin, also known as framycetin, is an aminoglycoside antibiotic that displays bactericidal activity against Gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against 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.<ref name=Fis2006>Template:Cite book</ref> Rutgers University was granted the patent for neomycin in 1957.<ref>Template:Cite patent</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Synthesis requires specific nutrient conditions in either stationary or submerged aerobic conditions. The compound is then isolated and purified from the bacterium.<ref>Template:Cite book</ref>

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.<ref>Template:Cite journal</ref>

Waksman and Lechevalier originally noted that neomycin was active against streptomycin-resistant bacteria as well as Mycobacterium tuberculosis, the causative agent for tuberculosis.<ref name="Waksman_1949b" /> 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.<ref>Template:Cite journal</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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).<ref>Template:DermNet</ref> Physicians sometimes recommend using antibiotic ointments without neomycin, such as Polysporin.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The following represents minimum inhibitory concentration (MIC) susceptibility data for a few medically significant Gram-negative bacteria.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• 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 patch test results (10.0%).<ref>Template:Cite journal</ref> It was named Allergen of the Year in 2010.<ref>McNamara, Damian. (2010). Neomycin Is Named Contact Allergen of the Year Template:Webarchive</ref> Neomycin is also a known GABA gamma-Aminobutyric acid antagonist and can be responsible for seizures and psychosis.<ref name="pmid219730">Template:Cite journal</ref> 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.<ref name="Langman, A 1994">Langman, A. Neomycin ototoxicity. Otolaryngology Head and Neck Surgery 1994, 110, 441-444.</ref> Hearing loss is caused by ear hair cell death, which occurs in response to treatment with neomycin.<ref name="Langman, A 1994"/> 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.Template: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.<ref>Template:Cite journal</ref>

Neomycin also exhibits a high binding affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of cell membranes.<ref name="pmid2537103">Template:Cite journal</ref>

Resistance

Neomycin resistance is conferred by either one of two kanamycin kinase genes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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. Currently, research is being performed to understand if derivatives of neomycin have the same antibiotic effects while still being effective against neomycin-resistant bacteria.<ref>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.</ref>

Biosynthetic pathway

Neomycin was first isolated from the Streptomyces fradiae and Streptomyces albogriseus in 1949 (NBRC 12773).<ref name = "Waksman_1949">Template:Cite journal</ref> 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.<ref name="Waksman_1949b" /> It is also thermostable and soluble in water (while insoluble in organic solvents).<ref name="Waksman_1949b">Template:Cite journal</ref> 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.<ref>Template:Cite book</ref>

Neomycin B is composed of four linked moieties: D-neosamine, 2-deoxystreptamine (2-DOS), D-ribose, and L-neosamine.Template: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).<ref>Template:Cite journal</ref> A deacetylase acting to remove the acetyl group on N-acetylglucosamine moieties of aminoglycoside intermediates (Neo16) remains to be clarified (sequence similar to BtrD).<ref>Template:Cite journal</ref>

Next is the attachment of the D-ribose via ribosylation of neamine, using 5-phosphoribosyl-1-diphosphate (PRPP) as the ribosyl donor (BtrL, BtrP);<ref>Template:Cite journal</ref> glycosyltransferase (potential homologues RibF, LivF, Parf) gene (Neo15).<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

File:Neomycin B.png

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.<ref name="pubchem.ncbi.nlm.nih.gov">National Center for Biotechnology Information Neomycin. https://pubchem.ncbi.nlm.nih.gov/compound/8378 (accessed Nov 5, 2023).</ref> 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.<ref name="pubchem.ncbi.nlm.nih.gov"/> Neomycin C can undergo enzymatic synthesis from ribostamycin.<ref name="pmid19713992">Template:Cite journal</ref>

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.<ref>Template:Cite book</ref> The quantities of these components in neomycin vary from lot-to-lot depending on the manufacturer and manufacturing process.<ref>Template:Cite journal</ref>

DNA binding

Aminoglycosides such as neomycin are known for their ability to bind to duplex RNA with high affinity.<ref>Template:Cite journal</ref> The association constant for neomycin with A-site RNA is in the 10⁹ M⁻¹ range.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>