Gramicidins

Gramicidin A ( Bacillus brevis )
Existing structural data : 1mag , 1nrm , 1jno , 1nru , 1mic
Mass / length primary structure	15 amino acids
Identifier
External IDs	CAS number : 1405-97-6
Drug information
ATC code	R02 AB30
DrugBank	BTD00036
Drug class	antibiotic
Transporter classification
TCDB	1.D.1
designation	Gramicidin A channel

Gramicidins are peptide - antibiotics from the bacterium Bacillus brevis . From the gram-positive two can be structurally and functionally different soil bacterium gramicidins isolate: gramicidin D (after the explorer D UBOS ) and gramicidin S (after the discoverer Georgi Gause S owjetunion ).

structure

Gramicidin D is a mixture of gramicidin A, B and C. It is a linear pentadeca peptide with the primary sequence: Formyl - L - Val ₁ - D - Gly ₂ - L - Ala ₃ - D - Leu ₄ - L -Ala ₅ - D -Val ₆ - L -Val ₇ - D -Val ₈ - L - Trp ₉ - D -Leu ₁₀ - L - Xxx ₁₁ - D -Leu ₁₂ - L -Trp ₁₃ - D -Leu ₁₄ - L -Trp ₁₅ - Ethanolamine , where gramicidin A contains tryptophan (Trp), gramicidin B phenylalanine (Phe) and gramicidin C tyrosine (Tyr) at position 11 in the peptide. The alternating stereochemical configuration ( L- and D -form) of the amino acids is necessary for the formation of a β-helix in membranes. The further subdivision into A1 and A2, B1 and B2 as well as C1 and C2 comes about because isoleucine can also occur in position 1 instead of valine .

Gramicidin S, on the other hand, is a cyclic deca peptide with the primary sequence : [- L -Val– L - Orn - L -Leu– D - Phe - L - Pro -] ₂ . Gramicidin J1 and gramicidin J2 also have a ring structure.

Structure of the linear gramicidins A, B and C

Linear gramicidins
HCO - X - Gly- L-Ala- D-Leu- L-Ala- D-Val- L-Val- D-Val- L-Trp- - D-Leu- Y - D-Leu- L-Trp- D-Leu- L-Trp- NH-CH 2 -CH 2 -OH
Gramicidin	Molecular formula	molar mass	X	Y
A1	C 99 H 140 N 20 O 17	1882	L-Val	L-Trp
A2	C 97 H 139 N 19 O 17	1896	L-Ile	L-Trp
B1	C 99 H 140 N 20 O 17	1843	L-Val	L-Phe
B2	C 100 H 142 N 20 O 17	1857	L-Ile	L-Phe
C1	C 97 H 139 N 19 O 18	1859	L-Val	L-Tyr
C2	C 98 H 141 N 19 O 18	1873	L-Ile	L-Tyr
Cyclic gramicidins
Gramicidin	Ring structure
S.	┌ L-Val- L-Orn- L-Leu- D-Phe- L-Pro- L-Val- L-Orn- L-Leu- D-Phe- L-Pro┐ └────────────────────────────────────── ──────────────────┘
J1	┌ L-Val- D-Orn- D-Phe- D-Leu- L-Phe- L-Pro- D-Orn┐ └───────────────────────────────────────┘
J2	┌ L-Val- L-Orn- D-Leu- D-Phe- L-Pro- D-Orn┐ └─────────────────────────────────┘

Discovery story

Gramicidin D was first isolated in 1940 by René Dubos and Gramicidin S for the first time in 1944 by Braschnikowa and Georgi Gause from the culture supernatant of Bacillus brevis . Gramicidin D itself is not synthesized on the ribosome , but via non- ribosomal peptide synthesis. The synthesis machinery consists of a cytoplasmic multienzyme complex. However, this synthesis is somewhat less precise than the ribosomal one, which is probably the reason for the differences in gramicidin A, B and C.

Mechanism of action

Its bactericidal effect as a pore-forming toxin comes about through the storage of the lipophilic molecule in cell membranes : two molecules of gramicidin form an ion channel between the cytoplasm and the outside of the cell. This channel is specific for monovalent (monovalent) cations such as e.g. B. potassium, but does not allow divalent (divalent) cations or anions through. This results in an unregulated ion flow in the direction of the respective concentration and electrochemical gradient that leads to cell death. Depending on the concentration, the effect ranges from a lowering of the membrane fluidity and activation / inhibition of membrane-based enzymes via changed ion permeability to complete destruction of the membrane. As a result, gramicidin is toxic to both prokaryotic and eukaryotic cells.

use

Drug

Gramicidin D is used as an antibiotic primarily in combination preparations for external use ( eyes , ears , nose , skin ). The medicinal substance ( non- proprietary name gramicidin) consists of at least 95% in total of the linear gramicidins A1, A2, B1, C1 and C2. Gramicidin A1 makes up the majority of this with at least 60%, while gramicidin B2 is a maximum of 2% impurity.

The naturally occurring mixture of gramicidin and tyrocidin is called tyrothricin . It is mainly used for infections in the oral cavity and throat (lozenges) or for wound treatment (gel / powder).

biochemistry

In research, gramicidin is used, among other things, in the electrophysiological examination of cells. With the so-called perforated patch technique (a variant of the patch clamp technique ), a glass pipette is filled with a conductive solution which also contains gramicidin. If the tip of this pipette is placed on a cell membrane, the gramicidin forms pores / channels in the membrane of the cell to be examined, creating a conductive contact between the measuring pipette and the cell. Since the resulting channels are permeable to ions, but not to larger cell components, the electrical properties of a cell can be measured without serious changes in the intracellular environment (with the conventional patch-clamp technique, on the other hand, the intracellular environment is greatly changed).

Contraindications

Gramicidin must not be used if there is any suspicion of a connection between the area of ​​application and the CSF space or meninges .

Finished medicinal products

Combination preparations

• with polymyxin-B and neomycin or bacitracin : Neosporin (CH), Polyspectran (D)
• with dexamethasone: Sofradex (CH)
• with fluocinonide , neomycin, nystatin: Mycolog (CH), Topsym polyvalent (CH)

Monopreparations

• only in a natural mixture with tyrocidin as tyrothricin : Dorithricin (D), Lemocin (D), Tyrosur (D)

literature

• BA Wallace: Gramicidin channels and pores . In: Annu. Rev. Biophys. Biophys. Chem. , Vol. 19, 1990, pp. 127-157. PMID 1694667 .
• Andrea Vescovi: Synthesis, structure and function investigation of THF-gramicidin hybrid ion channels . Logos Verlag, Berlin 2002, ISBN 3-8325-0068-5 .

Individual evidence

1. ^ RD Hotchkiss, RJ Dubos: Fractionation of the bactericidal agent from cultures of a soil bacillus . In: J. Biol. Chem. , Vol. 132, 1940, pp. 791-792. jbc.org (PDF)
2. ↑ RD Hotchkiss, RJ Dubos: Chemical Properties of bactericidal substances isolated from cultures of a soil bacillus . In: J. Biol. Chem. , Vol. 132, 1940, pp. 793-794. jbc.org (PDF)
3. ↑ GF Gause, MG Brazhnikova. In: Nature , Volume 154, 1944, p. 703.
4. ↑ Georgy Gause. ( Memento of the original from January 25, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Gause Journal 

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !