Gramicidin S

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Gramicidin S
File:GramicidinS.png
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PubChem CID
E number{{#property:P628}}
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Chemical and physical data
FormulaC60H92N12O10
Molar mass1140.7059 g/mol

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Gramicidin S or Gramicidin Soviet[1] is an antibiotic effective against some Gram positive and Gram negative bacteria as well as some fungi. It is a derivative of gramicidin, produced by the Gram positive bacterium Bacillus brevis. Gramicidin S is a cyclodecapeptide, constructed as two identical pentapeptides joined head to tail, formally written as cyclo(-Val-Orn-Leu-D-Phe-Pro-)2. That is to say, it forms a ring structure composed of five different amino acids, each one used twice within the structure.[2]Another interesting point is that it utilizes two amino acids uncommon in peptides: ornithine as well as the unnatural stereoisomer of phenylalanine. It is synthesized by gramicidin S synthetase.[3]

History

Gramicidin S was discovered by Russian microbiologist Georgyi Frantsevitch Gause and his wife Maria Brazhnikovain 1942. Within the year Gramicidin S was being used in Soviet military hospitals to treat infection and eventually found usage at the front lines of combat by 1946.[4]Gause was awarded the Stalin Prize for Medicine for his discovery in 1946. In 1944, Gramicind S was sent by the Soviet Ministry of Health to Great Britain via the International Red Cross in a collaborative effort to establish the exact structure. English chemist Richard Synge proved that the compound was an original antibiotic and a polypeptide using paper chromatography[5]. He would later go on to receive the Nobel Prize for his work in chromatography. The crystal structure was finally established by Dorothy Hodgkin and Gerchardt Schmidt. The importance of Gramicidin S and antibiotic research in general was so great that Gause was not persecuted during the period of Lysenkoism in the USSR, while many of his colleagues were being executed. Indeed, it was his need for developing new strains to mass produce antibiotics that allowed politically sanctioned collaborations with geneticists like Joseph Rapoport and Alexander Malinovsky, who would both actively participate in the downfall of Lysenkoism.[6]

Structure and Pharmacological effect

File:GS.png
Crystal structure of modified Gramicidin S. Modification includes Boc groups on the ornithine as well as methylation of select amide nitrogens to force cyclic conformation.[7]

Structurally, Gramicidin S differs from Gramicidin D, which is a linear peptide and forms a beta helix in cellular membranes. The mode of action is not entirely agreed upon, but it is generally accepted that it is the disruption of the barrier properties of cellular membranes which causes cell death. Recent research revels that Gramicind S interacts more so with with anionic membranes (such as those of bacteria) vs. zwitterionic membranes and more fluid membranes.[8] It has a molecular mass of ca. 1,140 and is a solid, usually encapsulated in two-percent sterile spirit solution. In vitro assays show it has a MIC of 5-15 μg/mL.[9]

Use

Gramicidin S has historically been employed as a topical antibiotic for the treatment of infections from superficial wounds. It exhibits strong antibiotic activity against a broad spectrum of Gram negative and Gram-positive bacteria and against several pathogenic fungi. Like Gramicidin D, Gramicidin S causes hemolysis at low concentrations, thus is not an effective drug for the treatment of systematic infections. Additionally, Gramicidin S has been employed as a spermicide and therapeutic for genital ulcers caused by sexually transmitted disease[10].

References

  1. Gause, G. F. & Brazhnikova, M. G. (1944). Nature (London), 154, 703.
  2. Llamas-Saiz, Antonio (2007), "Double-stranded helical twisted b-sheet channels in crystals of gramicidin S grown in the presence of trifluoroacetic and hydrochloric acids", Acta Crystallographica Section D, D63: 401–407, doi:10.1107/S0907444906056435
  3. Brick, Peter (1997), "Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S", The EMBO Journal, 16: 4174–4183, doi:10.1093/emboj/16.14.4174
  4. Konashev, Mikhail (2001), "The dicovery of Gramicidin S: the Intellectual Transformation of G.F. Gause from Biologist to Researcher of Antibiotics and on its Meaning for the Fate of Russian Genetics", Hist. Phil. Life Sci., 23: 137–150
  5. http://www.britannica.com/eb/article-9070753/RLM-Synge
  6. Konashev, Mikhail (2001), "The dicovery of Gramicidin S: the Intellectual Transformation of G.F. Gause from Biologist to Researcher of Antibiotics and on its Meaning for the Fate of Russian Genetics", Hist. Phil. Life Sci., 23: 137–150
  7. "Stereochemistry of Protected Ornithine Side Chains of Gramicidin S Derivatives: X-ray Crystal Structure of the Bis-Boc-tetra-N-methyl Derivative of Gramicidin S", J. Am. Chem. Soc.; (124): 12684 - 12688;, 2002;, doi:10.1021/ja020307t |first1= missing |last1= in Authors list (help); Check date values in: |year= (help)
  8. Ronald N. McElhaney, J. Bio. Chem. 280, pp. 2002–2011, 2005
  9. Peter Wipf, J. Am. Chem. Soc. 2005, 127, 5742-5743
  10. Krylov YuF (1993) Compendium of medicinal products of Russia. Inpharmchem Press, Moscow, p 343 [in Russian]

Acta Cryst. (2007). D63, 401-407 [ doi:10.1107/S0907444906056435 ]

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