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Gramicidin

August 17, 2023

Gramicidin, also called gramicidin D, is a mix of ionophoric antibiotics, gramicidin A, B and C, which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 isoforms, so the mix has 6 different types of gramicidin molecules. They can be extracted from Brevibacillus brevis soil bacteria. Gramicidins are linear peptides with 15 amino acids.[2] This is in contrast to unrelated gramicidin S, which is a cyclic peptide.

Gramicidin A head-to-head dimer
Identifiers
SymbolN/A
TCDB1.D.1
OPM superfamily65
OPM protein1grm
Gramicidin
Structure of gramicidin A, B, and C (click to enlarge)
Clinical data
ATC code
Identifiers
CAS Number
  • 1405-97-6 Y
PubChem CID
  • 16130140
DrugBank
  • DB00027 N
ChemSpider
  • 3076403 Y
UNII
  • 5IE62321P4
KEGG
  • D04369 Y
ChEMBL
  • ChEMBL557217 N
ECHA InfoCard100.014.355
Chemical and physical data
FormulaC99H140N20O17
Molar mass1882.332 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point229 to 230 °C (444 to 446 °F) [1]
Solubility in water0.006 mg/L[1]
  • C[C@@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC7=CNC8=CC=CC=C87)C(=O)NCCO)NC(=O)CNC(=O)[C@H](C(C)C)NC=O
  • InChI=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) Y
  • Key:IUAYMJGZBVDSGL-UHFFFAOYSA-N Y
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Medical uses

Gramicidins work as antibiotics against gram-positive bacteria like Bacillus subtilis and Staphylococcus aureus, but not well against gram-negative ones like E. coli.[3]

Gramicidins are used in medicinal lozenges for sore throat and in topical medicines to treat infected wounds. Gramicidins are often mixed with other antibiotics like tyrocidine and antiseptics.[4] Gramicidins are also used in eye drops for bacterial eye infections. In drops, they are often mixed with other antibiotics like polymyxin B or neomycin. Multiple antibiotics increase efficiency against various strains of bacteria.[5] Such eye-drops are also used to treat eye infections of animals, like horses.[6]

History

In 1939, René Dubos isolated the substance tyrothricin.[7][8] Later this was shown to be a mix of gramicidin and tyrocidine. These were the first antibiotics to be manufactured commercially.[8] Letter "D" in gramicidin D is short for "Dubos",[9] and was invented to differentiate the mix from gramicidin S.[10]

In 1964, the sequence of gramicidin A was determined by Reinhard Sarges and Bernhad Witkop.[11][12]

In 1971, the dimeric head-to-head structure of gramicidins was proposed by D. W. Urry.[13]

In 1993, the structure of the gramicidin head-to-head dimer in micelles and lipid bilayers was determined by solution and solid-state NMR.[14]

Structure and chemistry

Gramicidins A, B and C are nonribosomal peptides, thus they have no genes. They consist of 15 L- and D-amino acids. Their amino acid sequence is:[2]

formyl-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-ethanolamine

Y is L-tryptophan in gramicidin A, L-phenylalanine in B and L-tyrosine in C. X determines isoform. X is L-valine or L-isoleucine – in natural gramicidin mixes of A, B and C, about 5% of the total gramicidins are isoleucine isoforms.[2]

 
Gramicidin helices. Antiparallel (left) and parallel double helices and the helix dimer present in lipid bilayers. C and N are C- and N-terminals.[12]

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 dimers. 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 ion channel -type of ionophores.[12]

Gramicidin mixture is a crystalline solid. Its solubility in water is minimal, 6 mg/L, and it may form colloidal suspensions. It is soluble in small alcohols, acetic acid, pyridine, poorly soluble in acetone and dioxane, and practically insoluble in diethylether and hydrocarbons.[1]

Pharmacological effect

Gramicidins are ionophores. Their dimers form ion channel-like pores in cell membranes and cellular organelles of bacteria and animal cells.[15] Inorganic monovalent ions, such as potassium (K+) and sodium (Na+), can travel through these pores freely via diffusion. This destroys vital ion concentration differences, i.e. ion gradients, between membranes thereby killing the cell via various effects. For example, ion leak in mitochondria halts mitochondrial ATP production in cells with mitochondria.[16]

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.[3] Gramicidins are not used internally, as their significant intake may cause hemolysis and be toxic to the liver, kidney, meninges and olfactory system among other effects.[16]

References

  1. ^ a b c Budavari S (1996). The Merck index: an encyclopedia of chemicals, drugs, and biologicals (12th ed.). Merck. p. 712. ISBN 0911910123. OCLC 34552962.
  2. ^ a b c Kessler N, Schuhmann H, Morneweg S, Linne U, Marahiel MA (February 2004). "The linear pentadecapeptide gramicidin is assembled by four multimodular nonribosomal peptide synthetases that comprise 16 modules with 56 catalytic domains". The Journal of Biological Chemistry. 279 (9): 7413–9. doi:10.1074/jbc.M309658200. PMID 14670971.
  3. ^ a b Wang F, Qin L, Pace CJ, Wong P, Malonis R, Gao J (January 2012). "Solubilized gramicidin A as potential systemic antibiotics". ChemBioChem. 13 (1): 51–5. doi:10.1002/cbic.201100671. PMID 22113881. S2CID 4906040.
  4. ^ Palm J, Fuchs K, Stammer H, Schumacher-Stimpfl A, Milde J (December 2018). "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)". International Journal of Clinical Practice. 72 (12): e13272. doi:10.1111/ijcp.13272. PMC 6282512. PMID 30329199.
  5. ^ Bosscha MI, van Dissel JT, Kuijper EJ, Swart W, Jager MJ (January 2004). "The efficacy and safety of topical polymyxin B, neomycin and gramicidin for treatment of presumed bacterial corneal ulceration". The British Journal of Ophthalmology. 88 (1): 25–8. doi:10.1136/bjo.88.1.25. PMC 1771930. PMID 14693766.
  6. ^ Gilger BC, Allbaugh RA (2011). Equine ophthalmology (2nd ed.). Elsevier Saunders. pp. 111, 190. ISBN 9781437708462.
  7. ^ Dubos RJ (June 1939). "Studies on a bactericidal agent extracted from a soil bacillus: I. Preparation of the agent. Its activity in vitro". The Journal of Experimental Medicine. 70 (1): 1–10. doi:10.1084/jem.70.1.1. PMC 2133784. PMID 19870884.
  8. ^ a b Van Epps HL (February 2006). "René Dubos: unearthing antibiotics". The Journal of Experimental Medicine. 203 (2): 259. doi:10.1084/jem.2032fta. PMC 2118194. PMID 16528813.
  9. ^ Lum K (2017). "Exchange of gramicidin between lipid bilayers: implications for the mechanism of channel formation". Biophysical Journal. 113 (8): 1757–1767. Bibcode:2017BpJ...113.1757L. doi:10.1016/j.bpj.2017.08.049. ISSN 0006-3495. PMC 5647621. PMID 29045870.
  10. ^ "Gramicidin from Bacillus brevis product No. G 5002" (PDF). sigmaaldrich.com. 1997-09-06. Retrieved 2019-10-03.
  11. ^ Sarges R, Bernhard W (1964). "gramicidin A. IV. Primary sequence of valine and isoleucine gramicidin A". Journal of the American Chemical Society. 86 (9): 1862–1863. doi:10.1021/ja01063a049. ISSN 0002-7863.
  12. ^ a b c Meikle TG, Conn CE, Separovic F, Drummond CJ (2016). "Exploring the structural relationship between encapsulated antimicrobial peptides and the bilayer membrane mimetic lipidic cubic phase: studies with gramicidin A′". RSC Advances. 6 (73): 68685–68694. Bibcode:2016RSCAd...668685M. doi:10.1039/C6RA13658C.
  13. ^ Urry DW (March 1971). "The gramicidin A transmembrane channel: a proposed pi(L,D) helix". Proceedings of the National Academy of Sciences of the United States of America. 68 (3): 672–6. Bibcode:1971PNAS...68..672U. doi:10.1073/pnas.68.3.672. PMC 389014. PMID 5276779.
  14. ^ Ketchem RR, Hu W, Cross TA (September 1993). "High-resolution conformation of gramicidin A in a lipid bilayer by solid-state NMR". Science. 261 (5127): 1457–60. Bibcode:1993Sci...261.1457K. doi:10.1126/science.7690158. PMID 7690158.
  15. ^ Sorochkina AI, Plotnikov EY, Rokitskaya TI, Kovalchuk SI, Kotova EA, Sychev SV, et al. (2012). "N-terminally glutamate-substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler". PLOS ONE. 7 (7): e41919. Bibcode:2012PLoSO...741919S. doi:10.1371/journal.pone.0041919. PMC 3404012. PMID 22911866.
  16. ^ a b David JM, Rajasekaran AK (2015). "Gramicidin A: A New Mission for an Old Antibiotic". Journal of Kidney Cancer and VHL. 2 (1): 15–24. doi:10.15586/jkcvhl.2015.21. PMC 5345515. PMID 28326255.

August 17, 2023
gramicidin, also, called, gramicidin, ionophoric, antibiotics, gramicidin, which, make, about, respectively, each, isoforms, different, types, gramicidin, molecules, they, extracted, from, brevibacillus, brevis, soil, bacteria, linear, peptides, with, amino, a. Gramicidin also called gramicidin D is a mix of ionophoric antibiotics gramicidin A B and C which make up about 80 5 and 15 of the mix respectively Each has 2 isoforms so the mix has 6 different types of gramicidin molecules They can be extracted from Brevibacillus brevis soil bacteria Gramicidins are linear peptides with 15 amino acids 2 This is in contrast to unrelated gramicidin S which is a cyclic peptide Gramicidin A head to head dimerIdentifiersSymbolN ATCDB1 D 1OPM superfamily65OPM protein1grmGramicidinStructure of gramicidin A B and C click to enlarge Clinical dataATC codeR02AB30 WHO IdentifiersCAS Number1405 97 6 YPubChem CID16130140DrugBankDB00027 NChemSpider3076403 YUNII5IE62321P4KEGGD04369 YChEMBLChEMBL557217 NECHA InfoCard100 014 355Chemical and physical dataFormulaC 99H 140N 20O 17Molar mass1882 332 g mol 13D model JSmol Interactive imageMelting point229 to 230 C 444 to 446 F 1 Solubility in water0 006 mg L 1 SMILES C C H C O N C H CC C C C O N C H C C O N C H C C C C O N C H C C C C O N C H C C C C O N C H CC1 CNC2 CC CC C21 C O N C H CC C C C O N C H CC3 CNC4 CC CC C43 C O N C H CC C C C O N C H CC5 CNC6 CC CC C65 C O N C H CC C C C O N C H CC7 CNC8 CC CC C87 C O NCCO NC O CNC O C H C C C NC OInChI InChI 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 YKey IUAYMJGZBVDSGL UHFFFAOYSA N Y N Y what is this verify Contents 1 Medical uses 2 History 3 Structure and chemistry 4 Pharmacological effect 5 ReferencesMedical uses EditGramicidins work as antibiotics against gram positive bacteria like Bacillus subtilis and Staphylococcus aureus but not well against gram negative ones like E coli 3 Gramicidins are used in medicinal lozenges for sore throat and in topical medicines to treat infected wounds Gramicidins are often mixed with other antibiotics like tyrocidine and antiseptics 4 Gramicidins are also used in eye drops for bacterial eye infections In drops they are often mixed with other antibiotics like polymyxin B or neomycin Multiple antibiotics increase efficiency against various strains of bacteria 5 Such eye drops are also used to treat eye infections of animals like horses 6 History EditIn 1939 Rene Dubos isolated the substance tyrothricin 7 8 Later this was shown to be a mix of gramicidin and tyrocidine These were the first antibiotics to be manufactured commercially 8 Letter D in gramicidin D is short for Dubos 9 and was invented to differentiate the mix from gramicidin S 10 In 1964 the sequence of gramicidin A was determined by Reinhard Sarges and Bernhad Witkop 11 12 In 1971 the dimeric head to head structure of gramicidins was proposed by D W Urry 13 In 1993 the structure of the gramicidin head to head dimer in micelles and lipid bilayers was determined by solution and solid state NMR 14 Structure and chemistry EditGramicidins A B and C are nonribosomal peptides thus they have no genes They consist of 15 L and D amino acids Their amino acid sequence is 2 formyl 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 ethanolamineY is L tryptophan in gramicidin A L phenylalanine in B and L tyrosine in C X determines isoform X is L valine or L isoleucine in natural gramicidin mixes of A B and C about 5 of the total gramicidins are isoleucine isoforms 2 Gramicidin helices Antiparallel left and parallel double helices and the helix dimer present in lipid bilayers C and N are C and N terminals 12 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 dimers 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 ion channel type of ionophores 12 Gramicidin mixture is a crystalline solid Its solubility in water is minimal 6 mg L and it may form colloidal suspensions It is soluble in small alcohols acetic acid pyridine poorly soluble in acetone and dioxane and practically insoluble in diethylether and hydrocarbons 1 Pharmacological effect EditGramicidins are ionophores Their dimers form ion channel like pores in cell membranes and cellular organelles of bacteria and animal cells 15 Inorganic monovalent ions such as potassium K and sodium Na can travel through these pores freely via diffusion This destroys vital ion concentration differences i e ion gradients between membranes thereby killing the cell via various effects For example ion leak in mitochondria halts mitochondrial ATP production in cells with mitochondria 16 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 3 Gramicidins are not used internally as their significant intake may cause hemolysis and be toxic to the liver kidney meninges and olfactory system among other effects 16 References Edit a b c Budavari S 1996 The Merck index an encyclopedia of chemicals drugs and biologicals 12th ed Merck p 712 ISBN 0911910123 OCLC 34552962 a b c Kessler N Schuhmann H Morneweg S Linne U Marahiel MA February 2004 The linear pentadecapeptide gramicidin is assembled by four multimodular nonribosomal peptide synthetases that comprise 16 modules with 56 catalytic domains The Journal of Biological Chemistry 279 9 7413 9 doi 10 1074 jbc M309658200 PMID 14670971 a b Wang F Qin L Pace CJ Wong P Malonis R Gao J January 2012 Solubilized gramicidin A as potential systemic antibiotics ChemBioChem 13 1 51 5 doi 10 1002 cbic 201100671 PMID 22113881 S2CID 4906040 Palm J Fuchs K Stammer H Schumacher Stimpfl A Milde J December 2018 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 International Journal of Clinical Practice 72 12 e13272 doi 10 1111 ijcp 13272 PMC 6282512 PMID 30329199 Bosscha MI van Dissel JT Kuijper EJ Swart W Jager MJ January 2004 The efficacy and safety of topical polymyxin B neomycin and gramicidin for treatment of presumed bacterial corneal ulceration The British Journal of Ophthalmology 88 1 25 8 doi 10 1136 bjo 88 1 25 PMC 1771930 PMID 14693766 Gilger BC Allbaugh RA 2011 Equine ophthalmology 2nd ed Elsevier Saunders pp 111 190 ISBN 9781437708462 Dubos RJ June 1939 Studies on a bactericidal agent extracted from a soil bacillus I Preparation of the agent Its activity in vitro The Journal of Experimental Medicine 70 1 1 10 doi 10 1084 jem 70 1 1 PMC 2133784 PMID 19870884 a b Van Epps HL February 2006 Rene Dubos unearthing antibiotics The Journal of Experimental Medicine 203 2 259 doi 10 1084 jem 2032fta PMC 2118194 PMID 16528813 Lum K 2017 Exchange of gramicidin between lipid bilayers implications for the mechanism of channel formation Biophysical Journal 113 8 1757 1767 Bibcode 2017BpJ 113 1757L doi 10 1016 j bpj 2017 08 049 ISSN 0006 3495 PMC 5647621 PMID 29045870 Gramicidin from Bacillus brevis product No G 5002 PDF sigmaaldrich com 1997 09 06 Retrieved 2019 10 03 Sarges R Bernhard W 1964 gramicidin A IV Primary sequence of valine and isoleucine gramicidin A Journal of the American Chemical Society 86 9 1862 1863 doi 10 1021 ja01063a049 ISSN 0002 7863 a b c Meikle TG Conn CE Separovic F Drummond CJ 2016 Exploring the structural relationship between encapsulated antimicrobial peptides and the bilayer membrane mimetic lipidic cubic phase studies with gramicidin A RSC Advances 6 73 68685 68694 Bibcode 2016RSCAd 668685M doi 10 1039 C6RA13658C Urry DW March 1971 The gramicidin A transmembrane channel a proposed pi L D helix Proceedings of the National Academy of Sciences of the United States of America 68 3 672 6 Bibcode 1971PNAS 68 672U doi 10 1073 pnas 68 3 672 PMC 389014 PMID 5276779 Ketchem RR Hu W Cross TA September 1993 High resolution conformation of gramicidin A in a lipid bilayer by solid state NMR Science 261 5127 1457 60 Bibcode 1993Sci 261 1457K doi 10 1126 science 7690158 PMID 7690158 Sorochkina AI Plotnikov EY Rokitskaya TI Kovalchuk SI Kotova EA Sychev SV et al 2012 N terminally glutamate substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler PLOS ONE 7 7 e41919 Bibcode 2012PLoSO 741919S doi 10 1371 journal pone 0041919 PMC 3404012 PMID 22911866 a b David JM Rajasekaran AK 2015 Gramicidin A A New Mission for an Old Antibiotic Journal of Kidney Cancer and VHL 2 1 15 24 doi 10 15586 jkcvhl 2015 21 PMC 5345515 PMID 28326255 Retrieved from https en wikipedia org w index php title Gramicidin amp oldid 1151281732, wikipedia, 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