| Revision as of 15:46, 17 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456537057 of page Gramicidin for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL'). |
Latest revision as of 14:21, 2 October 2024 edit Lannster (talk | contribs)1 editm Changed solubility to be consistent with value in text. Previously was listed as 0.006 mg/L, which seems unrealistically low.Tag: Visual edit |
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{{Short description|Mix of ionophoric antibiotics}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Infobox protein family |
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|Symbol=N/A |
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|Name= |
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|image=Gramicidin A.gif |
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|width=300 |
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|caption=Gramicidin A head-to-head dimer |
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|Pfam= |
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|Pfam_clan= |
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|InterPro= |
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|SMART= |
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|PROSITE= |
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|MEROPS= |
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|SCOP= |
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|TCDB=1.D.1 |
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|OPM family=65 |
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|OPM protein=1grm |
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|CAZy= |
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|CDD= |
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}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 414063447 |
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| verifiedrevid = 461123422 |
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| image = Gramicidin A.gif |
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| image = Structure of Gramicidins A B C.png |
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| width = 300 |
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<!--Clinical data--> |
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| caption = Structure of gramicidin A, B, and C (click to enlarge) |
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| tradename = |
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<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}} |
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| Drugs.com = {{drugs.com|international|gramicidin}} |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| legal_AU = <!-- Unscheduled / S2 / S4 / S8 --> |
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| legal_UK = <!-- GSL / P / POM / CD --> |
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| legal_US = <!-- OTC / Rx-only --> |
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<!--Identifiers--> |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 1405-97-6 |
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| CAS_number = 1405-97-6 |
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| PubChem = 16130140 |
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| ATC_prefix = R02 |
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| ATC_prefix = R02 |
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| ATC_suffix = AB30 |
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| ATC_suffix = AB30 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = <!-- blanked - oldvalue: BTD00036 --> |
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| DrugBank = DB00027 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 3076403 |
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| ChemSpiderID = 3076403 |
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| KEGG = D04369 |
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| KEGG = D04369 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = <!-- blanked - oldvalue: 557217 --> |
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| ChEMBL = 557217 |
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<!--Chemical data-->| C = 99 |
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| C=99 | H=140 | N=20 | O=17 |
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| H = 140 |
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| molecular_weight = 1882.3 g/mol |
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| N = 20 |
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| smiles = O=C1N5C(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N3C(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC1Cc2ccccc2)CC(C)C)CCCN)C(C)C)CCC3)Cc4ccccc4)CC(C)C)CCCN)C(C)C)CCC5 |
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| O = 17 |
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| InChI = 1/C60H92N12O10/c1-35(2)31-43-53(75)67-45(33-39-19-11-9-12-20-39)59(81)71-29-17-25-47(71)55(77)70-50(38(7)8)58(80)64-42(24-16-28-62)52(74)66-44(32-36(3)4)54(76)68-46(34-40-21-13-10-14-22-40)60(82)72-30-18-26-48(72)56(78)69-49(37(5)6)57(79)63-41(23-15-27-61)51(73)65-43/h9-14,19-22,35-38,41-50H,15-18,23-34,61-62H2,1-8H3,(H,63,79)(H,64,80)(H,65,73)(H,66,74)(H,67,75)(H,68,76)(H,69,78)(H,70,77) |
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| molecular_weight = |
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| InChIKey = IUAYMJGZBVDSGL-UHFFFAOYAP |
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| SMILES = C(C(=O)N(CC(C)C)C(=O)N(C)C(=O)N(C(C)C)C(=O)N(C(C)C)C(=O)N(C(C)C)C(=O)N(CC1=CNC2=CC=CC=C21)C(=O)N(CC(C)C)C(=O)N(CC3=CNC4=CC=CC=C43)C(=O)N(CC(C)C)C(=O)N(CC5=CNC6=CC=CC=C65)C(=O)N(CC(C)C)C(=O)N(CC7=CNC8=CC=CC=C87)C(=O)NCCO)NC(=O)CNC(=O)(C(C)C)NC=O |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C60H92N12O10/c1-35(2)31-43-53(75)67-45(33-39-19-11-9-12-20-39)59(81)71-29-17-25-47(71)55(77)70-50(38(7)8)58(80)64-42(24-16-28-62)52(74)66-44(32-36(3)4)54(76)68-46(34-40-21-13-10-14-22-40)60(82)72-30-18-26-48(72)56(78)69-49(37(5)6)57(79)63-41(23-15-27-61)51(73)65-43/h9-14,19-22,35-38,41-50H,15-18,23-34,61-62H2,1-8H3,(H,63,79)(H,64,80)(H,65,73)(H,66,74)(H,67,75)(H,68,76)(H,69,78)(H,70,77) |
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| StdInChI = 1S/C60H92N12O10/c1-35(2)31-43-53(75)67-45(33-39-19-11-9-12-20-39)59(81)71-29-17-25-47(71)55(77)70-50(38(7)8)58(80)64-42(24-16-28-62)52(74)66-44(32-36(3)4)54(76)68-46(34-40-21-13-10-14-22-40)60(82)72-30-18-26-48(72)56(78)69-49(37(5)6)57(79)63-41(23-15-27-61)51(73)65-43/h9-14,19-22,35-38,41-50H,15-18,23-34,61-62H2,1-8H3,(H,63,79)(H,64,80)(H,65,73)(H,66,74)(H,67,75)(H,68,76)(H,69,78)(H,70,77) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = IUAYMJGZBVDSGL-UHFFFAOYSA-N |
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| StdInChIKey = IUAYMJGZBVDSGL-UHFFFAOYSA-N |
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| melting_point = 229 |
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| synonyms = Bacillus brevis gramicidin D |
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| melting_high = 230 |
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| melting_notes = <ref name=":m"/> |
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| solubility = 6 |
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| sol_units = mg/L<ref name=":m"/> |
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}} |
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}} |
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'''Gramicidin''', also called '''gramicidin D''', is a mix of ] ], '''gramicidin A''', '''B''' and '''C''', which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 ], so the mix has 6 different types of gramicidin molecules. They can be extracted from '']'' soil bacteria. Gramicidins are linear ]s with 15 ].<ref name=":0"/> This is in contrast to unrelated ], which is a cyclic peptide. |
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==Medical uses== |
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Gramicidins work as antibiotics against ] bacteria like '']'' and '']'', but not well against gram-negative ones like '']''.<ref name=":2">{{cite journal | vauthors = Wang F, Qin L, Pace CJ, Wong P, Malonis R, Gao J | title = Solubilized gramicidin A as potential systemic antibiotics | journal = ChemBioChem | volume = 13 | issue = 1 | pages = 51–5 | date = January 2012 | pmid = 22113881 | doi = 10.1002/cbic.201100671 | s2cid = 4906040 }}</ref> |
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Gramicidins are used in medicinal ] for sore throat and in topical medicines to treat infected wounds. Gramicidins are often mixed with other antibiotics like ] and ].<ref>{{cite journal | vauthors = Palm J, Fuchs K, Stammer H, Schumacher-Stimpfl A, Milde J | title = Efficacy and safety of a triple active sore throat lozenge in the treatment of patients with acute pharyngitis: Results of a multi-centre, randomised, placebo-controlled, double-blind, parallel-group trial (DoriPha) | journal = International Journal of Clinical Practice | volume = 72 | issue = 12 | pages = e13272 | date = December 2018 | pmid = 30329199 | pmc = 6282512 | doi = 10.1111/ijcp.13272 }}</ref> Gramicidins are also used in ] for bacterial eye infections. In drops, they are often mixed with other antibiotics like ] or ]. Multiple antibiotics increase efficiency against various strains of bacteria.<ref>{{cite journal | vauthors = Bosscha MI, van Dissel JT, Kuijper EJ, Swart W, Jager MJ | title = The efficacy and safety of topical polymyxin B, neomycin and gramicidin for treatment of presumed bacterial corneal ulceration | journal = The British Journal of Ophthalmology | volume = 88 | issue = 1 | pages = 25–8 | date = January 2004 | pmid = 14693766 | pmc = 1771930 | doi = 10.1136/bjo.88.1.25 }}</ref> Such eye-drops are also used to treat eye infections of animals, like horses.<ref>{{cite book|title=Equine ophthalmology|vauthors=Gilger BC, Allbaugh RA |publisher=Elsevier Saunders |year=2011 |isbn=9781437708462 |edition=2nd |pages=111, 190}}</ref> |
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==History== |
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In 1939, ] isolated the substance ].<ref>{{cite journal | vauthors = Dubos RJ | title = Studies on a bactericidal agent extracted from a soil bacillus: I. Preparation of the agent. Its activity in vitro | journal = The Journal of Experimental Medicine | volume = 70 | issue = 1 | pages = 1–10 | date = June 1939 | pmid = 19870884 | pmc = 2133784 | doi = 10.1084/jem.70.1.1 }}</ref><ref name=":3">{{cite journal | vauthors = Van Epps HL | title = René Dubos: unearthing antibiotics | journal = The Journal of Experimental Medicine | volume = 203 | issue = 2 | pages = 259 | date = February 2006 | pmid = 16528813 | pmc = 2118194 | doi = 10.1084/jem.2032fta }}</ref> Later this was shown to be a mix of gramicidin and ]. These were the first antibiotics to be manufactured commercially.<ref name=":3"/> Letter "D" in gramicidin D is short for "Dubos",<ref>{{Cite journal|vauthors=Lum K|display-editors=etal|date=2017|title=Exchange of gramicidin between lipid bilayers: implications for the mechanism of channel formation|journal=Biophysical Journal|volume=113|issue=8|pages=1757–1767|doi=10.1016/j.bpj.2017.08.049|issn=0006-3495|pmc=5647621|pmid=29045870|bibcode=2017BpJ...113.1757L}}</ref> and was invented to differentiate the mix from ].<ref>{{Cite web|url=https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/2/g5002pis.pdf|title=Gramicidin from Bacillus brevis product No. G 5002|date=1997-09-06|website=sigmaaldrich.com|access-date=2019-10-03}}</ref> |
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In 1964, the sequence of gramicidin A was determined by Reinhard Sarges and Bernhad Witkop.<ref>{{Cite journal|vauthors=Sarges R, Bernhard W|date=1964|title=gramicidin A. IV. Primary sequence of valine and isoleucine gramicidin A|journal=Journal of the American Chemical Society|volume=86|issue=9|pages=1862–1863|doi=10.1021/ja01063a049|issn=0002-7863}}</ref><ref name=":1"/> |
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In 1971, the dimeric head-to-head structure of gramicidins was proposed by D. W. Urry.<ref>{{cite journal | vauthors = Urry DW | title = The gramicidin A transmembrane channel: a proposed pi(L,D) helix | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 3 | pages = 672–6 | date = March 1971 | pmid = 5276779 | pmc = 389014 | doi = 10.1073/pnas.68.3.672 | bibcode = 1971PNAS...68..672U | doi-access = free }}</ref> |
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In 1993, the structure of the gramicidin head-to-head dimer in ] and ]s was determined by solution and ].<ref>{{cite journal | vauthors = Ketchem RR, Hu W, Cross TA | title = High-resolution conformation of gramicidin A in a lipid bilayer by solid-state NMR | journal = Science | volume = 261 | issue = 5127 | pages = 1457–60 | date = September 1993 | pmid = 7690158 | doi = 10.1126/science.7690158 | url = https://www.science.org/doi/abs/10.1126/science.7690158 | bibcode = 1993Sci...261.1457K }}</ref> |
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==Structure and chemistry== |
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Gramicidins A, B and C are ]s, thus they have no ]s. They consist of 15 L- and D-amino acids. Their amino acid sequence is:<ref name=":0">{{cite journal | vauthors = Kessler N, Schuhmann H, Morneweg S, Linne U, Marahiel MA | title = The linear pentadecapeptide gramicidin is assembled by four multimodular nonribosomal peptide synthetases that comprise 16 modules with 56 catalytic domains | journal = The Journal of Biological Chemistry | volume = 279 | issue = 9 | pages = 7413–9 | date = February 2004 | pmid = 14670971 | doi = 10.1074/jbc.M309658200 | doi-access = free }}</ref> |
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:]-L-'''X'''-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-'''Y'''-D-Leu-L-Trp-D-Leu-L-Trp-] |
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Y is L-] in gramicidin A, L-] in B and L-] in C. X determines ]. X is L-] or L-] – in natural gramicidin mixes of A, B and C, about 5% of the total gramicidins are isoleucine isoforms.<ref name=":0"/> |
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]s.<ref name=":1">{{cite journal|vauthors=Meikle TG, Conn CE, Separovic F, Drummond CJ |date=2016|title=Exploring the structural relationship between encapsulated antimicrobial peptides and the bilayer membrane mimetic lipidic cubic phase: studies with gramicidin A′|journal=RSC Advances |volume=6 |issue=73 |pages=68685–68694 |doi=10.1039/C6RA13658C |bibcode=2016RSCAd...668685M|doi-access=free }}</ref>]] |
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Gramicidins form helices. The alternating pattern of D- and L-amino acids is important for the formation of these structures. Helices occur most often as head-to-head ]. 2 gramicidins can also form antiparallel or parallel double helices, especially in organic solvents. Dimers are long enough to span cellular lipid bilayers and thus function as ] -type of ]s.<ref name=":1"/> |
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Gramicidin mixture is a crystalline solid. Its solubility in water is minimal, 6 mg/L, and it may form ]al suspensions. It is soluble in small ]s, ], ], poorly soluble in ] and ], and practically insoluble in ] and ].<ref name=":m">{{Cite book|title=The Merck index: an encyclopedia of chemicals, drugs, and biologicals|vauthors=Budavari S|publisher=Merck|year=1996|isbn=0911910123|edition=12th|pages=712|oclc=34552962|display-editors=etal}}</ref> |
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==Pharmacological effect== |
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Gramicidins are ]s. Their ] form ]-like pores in ] and ] of bacteria and animal cells.<ref>{{cite journal | vauthors = Sorochkina AI, Plotnikov EY, Rokitskaya TI, Kovalchuk SI, Kotova EA, Sychev SV, Zorov DB, Antonenko YN | display-authors = 6 | title = N-terminally glutamate-substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler | journal = PLOS ONE | volume = 7 | issue = 7 | pages = e41919 | date = 2012 | pmid = 22911866 | pmc = 3404012 | doi = 10.1371/journal.pone.0041919 | bibcode = 2012PLoSO...741919S | doi-access = free }}</ref> ] ]s, such as ] (K<sup>+</sup>) and ] (Na<sup>+</sup>), can travel through these pores freely via ]. This destroys vital ion concentration differences, i.e. ]s, between membranes thereby killing the cell via various effects. For example, ion leak in ] halts mitochondrial ] production in cells with mitochondria.<ref name=":k">{{cite journal | vauthors = David JM, Rajasekaran AK | title = Gramicidin A: A New Mission for an Old Antibiotic | journal = Journal of Kidney Cancer and VHL | volume = 2 | issue = 1 | pages = 15–24 | date = 2015 | pmid = 28326255 | pmc = 5345515 | doi = 10.15586/jkcvhl.2015.21 }}</ref> |
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Gramicidins can be used as topical antibiotic medications in low doses, even though they are potentially lethal for human cells. Bacteria die at lower gramicidin concentrations than human cells.<ref name=":2"/> Gramicidins are not used internally, as their significant intake may cause ] and be toxic to the liver, kidney, ] and ] among other effects.<ref name=":k"/> |
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==References== |
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{{reflist}} |
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{{Throat preparations}} |
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{{Cell wall disruptive antibiotics}} |
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{{Membrane proteins}} |
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{{Non-ribosomally synthesized channels}} |
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] |
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] |
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] |