Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Neomycin: Difference between pages

{{Short description|Type of antibiotic}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 462259305

| IUPAC_name = (2''RS'',3''S'',4''S'',5''R'')-5-Amino-2-(aminomethyl)-6-((2''R'',3''S'',4''R'',5''S'')-5-((1''R'',2''R'',5''R'',6''R'')-3,5-diamino-2-((2''R'',3''S'',4''R'',5''S'')-3-amino-6-(aminomethyl)-4,5-dihydroxytetrahydro-2''H''-pyran-2-yloxy)-6-hydroxycyclohexyloxy)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yloxy)tetrahydro-2''H''-pyran-3,4-diol

| image2 = Neomycin ball-and-stick.png

| pregnancy_US = D

| legal_US = Rx-only

| legal_US_comment = but OTC in [[Neosporin]] and similar ointments

| routes_of_administration = [[Topical]], [[Mouth|oral]]

| bioavailability = None

| protein_bound = N/A

| metabolism = N/A

| CAS_number_Ref = {{cascite|correct|??}}

| ATC_supplemental = {{ATC|A07|AA01}}, {{ATC|B05|CA09}}, {{ATC|D06|AX04}}, {{ATC|J01|GB05}}, {{ATC|R02|AB01}}, {{ATC|S01|AA03}}, {{ATC|S02|AA07}}, {{ATC|S03|AA01}}

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 449118

| synonyms =

<!--Chemical data-->

| C=23 | H=46 | N=6 | O=13

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = PGBHMTALBVVCIT-DPNHOFNISA-N

<!-- Definition and medical uses -->

'''Neomycin''' 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 sugar]]s connected by [[glycosidic bond]]s.

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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>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=507 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA507 |language=en |access-date=2020-05-25 |archive-date=2020-08-01 |archive-url=https://web.archive.org/web/20200801185612/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA507 |url-status=live }}</ref> Rutgers University was granted the patent for neomycin in 1957.<ref>{{Cite patent | country = US | number = 2799620 | title = Neomycin and process of preparation | inventor = Waksman SA, Lechevalier HA | assign1 = Rutgers Research and Educational Foundation | gdate = 18 July 1957 | postscript = . }}</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>{{cite web|url=http://nobelprize.org/nobel_prizes/medicine/laureates/1952/waksman-bio.html|title=The Nobel Prize in Physiology or Medicine 1952|publisher=Nobel Foundation|access-date=2008-10-29|archive-date=2018-06-19|archive-url=https://web.archive.org/web/20180619213821/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1952/waksman-bio.html|url-status=live}}</ref> Synthesis requires specific nutrient conditions in either stationary or submerged aerobic conditions. The compound is then isolated and purified from the bacterium.<ref>{{cite book | chapter = Neomycin | title = Pharmaceutical Manufacturing Encyclopedia | edition = 3rd | volume = 3 | date = 2007 | pages = 2415–2416 }}</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, especially before [[Gastrointestinal tract|gastrointestinal]] [[Digestive system surgery|surgery]].{{citation needed|date=March 2023}}

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 [[aminoglycoside]]s. The exception is when neomycin is included, in small quantities, as a preservative in some vaccines – typically 25&nbsp;μg per dose.<ref>{{cite journal | vauthors = Heidary N, Cohen DE | title = Hypersensitivity reactions to vaccine components | journal = Dermatitis | volume = 16 | issue = 3 | pages = 115–20 | date = September 2005 | pmid = 16242081 | doi = 10.1097/01206501-200509000-00004 | s2cid = 31248441 }}</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>{{DermNet|dermatitis/neomycin-allergy}}</ref> Physicians sometimes recommend using antibiotic ointments without neomycin, such as [[Polysporin]].<ref>{{cite web |url=http://www.dermadoctor.com/article_Your-Medicine-Cabinet_43.html |title=Your Medicine Cabinet |publisher=DERMAdoctor.com, Inc. |access-date=2008-10-19 |url-status=dead |archive-url=https://web.archive.org/web/20090709093022/http://www.dermadoctor.com/article_Your-Medicine-Cabinet_43.html |archive-date=2009-07-09}}</ref> The following represents [[minimum inhibitory concentration]] (MIC) susceptibility data for a few medically significant Gram-negative bacteria.<ref>{{cite web |url=http://www.toku-e.com/Assets/MIC/Neomycin%20sulfate%20EP.pdf |title=Neomycin sulfate, EP Susceptibility and Minimum Inhibitory Concentration (MIC) Data |publisher=TOKU-E |access-date=2014-03-31 |archive-date=2015-12-22 |archive-url=https://web.archive.org/web/20151222095539/http://www.toku-e.com/Assets/MIC/Neomycin%20sulfate%20EP.pdf |url-status=live }}</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>{{cite journal | vauthors = Zug KA, Warshaw EM, Fowler JF, Maibach HI, Belsito DL, Pratt MD, Sasseville D, Storrs FJ, Taylor JS, Mathias CG, Deleo VA, Rietschel RL, Marks J | display-authors = 6 | title = Patch-test results of the North American Contact Dermatitis Group 2005-2006 | journal = Dermatitis | volume = 20 | issue = 3 | pages = 149–60 | year = 2009 | pmid = 19470301 | doi = 10.2310/6620.2009.08097 | s2cid = 24088485 }}</ref> It was named [[Allergen of the Year]] in 2010.<ref>McNamara, Damian. (2010). [http://www.edermatologynews.com/shared/shared-articles/neomycin-is-named-contact-allergen-of-the-year/4d105dda2788039dae9d166eac96393b.html Neomycin Is Named Contact Allergen of the Year] {{Webarchive|url=https://archive.today/20150422003106/http://www.edermatologynews.com/shared/shared-articles/neomycin-is-named-contact-allergen-of-the-year/4d105dda2788039dae9d166eac96393b.html|date=2015-04-22}}</ref> Neomycin is also a known GABA [[gamma-Aminobutyric acid|''gamma''-Aminobutyric acid]] antagonist and can be responsible for seizures and psychosis.<ref name="pmid219730">{{cite journal | vauthors = Lee C, de Silva AJ | title = Interaction of neuromuscular blocking effects of neomycin and polymyxin B | journal = Anesthesiology | volume = 50 | issue = 3 | pages = 218–20 | date = March 1979 | pmid = 219730 | doi = 10.1097/00000542-197903000-00010 | s2cid = 13551808 }}</ref> Like other aminoglycosides, neomycin has been shown to be [[Ototoxicity|ototoxic]], causing [[tinnitus]], hearing loss, and [[vestibular system|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.{{citation needed|date=March 2023}}

==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>{{cite journal | vauthors = Mehta R, Champney WS | title = Neomycin and paromomycin inhibit 30S ribosomal subunit assembly in Staphylococcus aureus | journal = Current Microbiology | volume = 47 | issue = 3 | pages = 237–43 | date = September 2003 | pmid = 14570276 | doi = 10.1007/s00284-002-3945-9 | s2cid = 23170091 }}</ref>

Neomycin also exhibits a high binding affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid component of cell membranes.<ref name="pmid2537103">{{cite journal | vauthors = Gabev E, Kasianowicz J, Abbott T, McLaughlin S | title = Binding of neomycin to phosphatidylinositol 4,5-bisphosphate (PIP2) | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 979 | issue = 1 | pages = 105–12 | date = February 1989 | pmid = 2537103 | doi = 10.1016/0005-2736(89)90529-4 }}</ref>

===Resistance===

Neomycin resistance is conferred by either one of two [[kanamycin kinase]] genes.<ref>{{cite web |url= http://www.bio.net/bionet/mm/methods/1999-March/073912.html |title= G418/neomycin-cross resistance? |access-date= 2008-10-19 |archive-date= 2009-06-25 |archive-url= https://web.archive.org/web/20090625211444/http://www.bio.net/bionet/mm/methods/1999-March/073912.html |url-status= live }}</ref> Genes conferring neomycin-resistance are commonly included in DNA [[plasmid]]s used to establish stable mammalian [[cell line]]s 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">{{cite journal | vauthors = Waksman SA, Lechevalier HA, Harris DA | title = Neomycin—Production and Antibiotic Properties 123 | journal = The Journal of Clinical Investigation | volume = 28 | issue = 5 Pt 1 | pages = 934–9 | date = September 1949 | pmid = 16695766 | pmc = 438928 | doi = 10.1172/JCI102182 }}</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">{{cite journal | vauthors = Waksman SA, Lechevalier HA | title = Neomycin, a New Antibiotic Active against Streptomycin-Resistant Bacteria, including Tuberculosis Organisms | journal = Science | location = New York, N.Y. | volume = 109 | issue = 2830 | pages = 305–7 | date = March 1949 | pmid = 17782716 | doi = 10.1126/science.109.2830.305 | bibcode = 1949Sci...109..305W }}</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>{{cite book | vauthors = Dewick M |title=Medicinal natural products: a biosynthetic approach|date=March 2009|publisher=John Wiley and Sons Ltd. |location=The Atrium, Southern Gate, Chichester, West Sussex, United Kingdom |isbn=978-0-470-74168-9 |pages=508, 510, 511 |edition=3rd }}</ref>

Neomycin B is composed of four linked moieties: <small>D</small>-neosamine, 2-deoxystreptamine (2-DOS), <small>D</small>-ribose, and <small>L</small>-neosamine.{{citation needed|date=March 2023}}

Neomycin A, also called neamine, contains <small>D</small>-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>{{cite journal | vauthors = Kudo F, Yamamoto Y, Yokoyama K, Eguchi T, Kakinuma K | title = Biosynthesis of 2-deoxystreptamine by three crucial enzymes in Streptomyces fradiae NBRC 12773 | journal = The Journal of Antibiotics | volume = 58 | issue = 12 | pages = 766–74 | date = December 2005 | pmid = 16506694 | doi = 10.1038/ja.2005.104 | doi-access = free }}</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>{{cite journal | vauthors = Park JW, Park SR, Nepal KK, Han AR, Ban YH, Yoo YJ, Kim EJ, Kim EM, Kim D, Sohng JK, Yoon YJ | display-authors = 6 | title = Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation | journal = Nature Chemical Biology | volume = 7 | issue = 11 | pages = 843–52 | date = October 2011 | pmid = 21983602 | doi = 10.1038/nchembio.671 }}</ref>

Next is the attachment of the <small>D</small>-ribose via [[ribosylation]] of neamine, using 5-phosphoribosyl-1-diphosphate (PRPP) as the ribosyl donor (BtrL, BtrP);<ref>{{cite journal | vauthors = Kudo F, Fujii T, Kinoshita S, Eguchi T | title = Unique O-ribosylation in the biosynthesis of butirosin | journal = Bioorganic & Medicinal Chemistry | volume = 15 | issue = 13 | pages = 4360–8 | date = July 2007 | pmid = 17482823 | doi = 10.1016/j.bmc.2007.04.040 }}</ref> glycosyltransferase (potential homologues RibF, LivF, Parf) gene (Neo15).<ref>{{cite journal | vauthors = Fan Q, Huang F, Leadlay PF, Spencer JB | title = The neomycin biosynthetic gene cluster of Streptomyces fradiae NCIMB 8233: genetic and biochemical evidence for the roles of two glycosyltransferases and a deacetylase | journal = Organic & Biomolecular Chemistry | volume = 6 | issue = 18 | pages = 3306–14 | date = September 2008 | pmid = 18802637 | doi = 10.1039/B808734B | s2cid = 29942953 }}</ref>

Neosamine B (<small>L</small>-neosamine B) is most likely biosynthesized in the same manner as the neosamine C (<small>D</small>-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>{{cite journal | vauthors = Llewellyn NM, Spencer JB | title = Biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics | journal = Natural Product Reports | volume = 23 | issue = 6 | pages = 864–74 | date = December 2006 | pmid = 17119636 | doi = 10.1039/B604709M }}</ref>

[[File:Neomycin B.png|thumb|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">{{cite journal | vauthors = Kudo F, Kawashima T, Yokoyama K, Eguchi T | title = Enzymatic preparation of neomycin C from ribostamycin | journal = The Journal of Antibiotics | volume = 62 | issue = 11 | pages = 643–6 | date = November 2009 | pmid = 19713992 | doi = 10.1038/ja.2009.88 | doi-access = free }}</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>{{cite book | vauthors = Cammack R, Attwood TK, Campbell PN, Parish JH, Smith AD, Stirling JL, Vella F | title = Oxford Dictionary of Biochemistry and Molecular Biology | edition = 2nd | chapter = neomycin | publisher = Oxford University Press | date = 2006 | pages = 453 }}</ref> The quantities of these components in neomycin vary from lot-to-lot depending on the manufacturer and manufacturing process.<ref>{{cite journal | vauthors = Tsuji K, Robertson JH, Baas R, McInnis DJ | title = Comparative study of responses to neomycins B and C by microbiological and gas-liquid chromatographic assay methods | journal = Applied Microbiology | volume = 18 | issue = 3 | pages = 396–8 | date = September 1969 | pmid = 4907002 | pmc = 377991 | doi = 10.1128/AEM.18.3.396-398.1969 }}</ref>

==DNA binding==

Aminoglycosides such as neomycin are known for their ability to bind to duplex RNA with high affinity.<ref>{{cite journal | vauthors = Jin Y, Watkins D, Degtyareva NN, Green KD, Spano MN, [[Sylvie Garneau-Tsodikova|Garneau-Tsodikova S]], Arya DP | title = Arginine-linked neomycin B dimers: synthesis, rRNA binding, and resistance enzyme activity | journal = MedChemComm | volume = 7 | issue = 1 | pages = 164–169 | date = January 2016 | pmid = 26811742 | pmc = 4722958 | doi = 10.1039/C5MD00427F }}</ref> The association constant for neomycin with A-site RNA is in the 10⁹ M⁻¹ range.<ref>{{cite journal | vauthors = Kaul M, Pilch DS | title = Thermodynamics of aminoglycoside-rRNA recognition: the binding of neomycin-class aminoglycosides to the A site of 16S rRNA | journal = Biochemistry | volume = 41 | issue = 24 | pages = 7695–706 | date = June 2002 | pmid = 12056901 | doi = 10.1021/bi020130f }}</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>{{cite journal | vauthors = Arya DP, Coffee RL | title = DNA triple helix stabilization by aminoglycoside antibiotics | journal = Bioorganic & Medicinal Chemistry Letters | volume = 10 | issue = 17 | pages = 1897–9 | date = September 2000 | pmid = 10987412 | doi = 10.1016/S0960-894X(00)00372-3 }}</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>{{cite journal | vauthors = Arya DP, Coffee RL, Charles I | title = Neomycin-induced hybrid triplex formation | journal = Journal of the American Chemical Society | volume = 123 | issue = 44 | pages = 11093–4 | date = November 2001 | pmid = 11686727 | doi = 10.1021/ja016481j }}</ref>

== References ==

{{Reflist}}

{{Stomatological preparations}}

{{Antidiarrheals, intestinal anti-inflammatory and anti-infective agents}}

{{Antibiotics and chemotherapeutics for dermatological use}}

{{Protein synthesis inhibitor antibiotics}}

{{Throat preparations}}

{{Otologicals}}

[[Category:Aminoglycoside antibiotics]]

[[Category:Cell culture reagents]]

[[Category:DNA-binding substances]]

[[Category:Otologicals]]