Gramicidin

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Gramicidin A.gif
Gramicidin A head-to-head dimer
Identifiers
SymbolN/A
TCDB 1.D.1
OPM superfamily 65
OPM protein 1grm
Gramicidin
Structure of Gramicidins A B C.png
Structure of gramicidin A, B, and C (click to enlarge)
Clinical data
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.014.355 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C99H140N20O17
Molar mass 1882.332 g·mol−1
3D model (JSmol)
Melting point 229 to 230 °C (444 to 446 °F) [1]
Solubility in water 0.006 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) Yes check.svgY
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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.

Contents

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

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]

Related Research Articles

Peptidoglycan or murein is a polysaccharide consisting of amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane of most bacteria, forming the cell wall. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is a peptide chain of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. Peptidoglycan is also involved in binary fission during bacterial cell reproduction. L-form bacteria and mycoplasmas, both lacking peptidoglycan cell walls, do not proliferate by binary fission, but by a budding mechanism.

<span class="mw-page-title-main">Membrane protein</span> Proteins that are part of, or interact with, biological membranes

Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane and can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane. Peripheral membrane proteins are transiently associated with the cell membrane.

<span class="mw-page-title-main">Transmembrane protein</span> Protein spanning across a biological membrane

A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

<span class="mw-page-title-main">Proteinogenic amino acid</span> Amino acid that is incorporated biosynthetically into proteins during translation

Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation. The word "proteinogenic" means "protein creating". Throughout known life, there are 22 genetically encoded (proteinogenic) amino acids, 20 in the standard genetic code and an additional 2 that can be incorporated by special translation mechanisms.

<span class="mw-page-title-main">ATP-binding cassette transporter</span> Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

<span class="mw-page-title-main">Antimicrobial peptides</span>

Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.

<span class="mw-page-title-main">Gramicidin S</span> Chemical compound

Gramicidin S or Gramicidin Soviet is an antibiotic that is effective against some gram-positive and gram-negative bacteria as well as some fungi.

<span class="mw-page-title-main">Tyrocidine</span> Chemical compound

Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D. Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host B. brevis is thought to be regulation of sporulation.

<span class="mw-page-title-main">Surfactin</span> Chemical compound

Surfactin is a very powerful surfactant commonly used as an antibiotic. It is a bacterial cyclic lipopeptide, largely prominent for its exceptional surfactant power. Its amphiphilic properties help this substance to survive in both hydrophilic and hydrophobic environments. It is an antibiotic produced by the Gram-positive endospore-forming bacteria Bacillus subtilis. In the course of various studies of its properties, surfactin was found to exhibit effective characteristics like antibacterial, antiviral, antifungal, anti-mycoplasma and hemolytic activities.

<span class="mw-page-title-main">Cecropin</span>

Cecropins are antimicrobial peptides. They were first isolated from the hemolymph of Hyalophora cecropia, whence the term cecropin was derived. Cecropins lyse bacterial cell membranes; they also inhibit proline uptake and cause leaky membranes.

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.

Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

Gramicidin B is part of the collective Gramicidin D that is an antibiotic obtained from a soil microbe- Bacillus brevis. This antibiotic forms channels in the cell membrane through which cations inside the cell begin to leave, thus disrupting the ion potential and eventually killing the cell. Gramicidin B makes up 6% of Gramicidin D while Gramicidin A and C make up 80% and 14% respectively. Gramicidin D is a linear pentadecapeptide made up of 15 amino acids. The 11th amino acid in these chains leads to the three different types of gramicidins. Gramicindin A contains tryptophan in the 11th position while B and C have phenylalanine and tyrosine respectively.

<span class="mw-page-title-main">WALP peptide</span> Class of peptides used for studying lipid membranes

WALP peptides are a class of synthesized, membrane-spanning α-helices composed of tryptophan (W), alanine (A), and leucine (L) amino acids. They are designed to study properties of proteins in lipid membranes such as orientation, extent of insertion, and hydrophobic mismatch.

<span class="mw-page-title-main">Cell membrane</span> Biological membrane that separates the interior of a cell from its outside environment

The cell membrane is a biological membrane that separates and protects the interior of all cells from the outside environment. The cell membrane consists of a lipid bilayer, made up of two layers of phospholipids with cholesterols interspersed between them, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as membrane transporters, and peripheral proteins that loosely attach to the outer (peripheral) side of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment. Glycolipids embedded in the outer lipid layer serve a similar purpose. The cell membrane controls the movement of substances in and out of cells and organelles, being selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate layer called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.

<span class="mw-page-title-main">Bacterial Leucine Transporter</span>

Bacterial Leucine Transporter (LeuT) is a bundled twelve alpha helix protein which belongs to the family of transporters that shuttle amino acids in and out of bacterial cells. Specialized in small hydrophobic amino acids such as leucine and alanine, this transporter is powered by the gradient of sodium ions that is normally maintained by healthy cells across their membranes. LeuT acts as a symporter, which means that it links the passage of a sodium ion across the cell membrane with the transport of the amino acid in the same direction. It was first crystallized to understand the inner molecular mechanisms of antidepressant's work since it has a close resemblance with the human neurotransmitter transporters that these drugs block, thus inhibiting the reuptake of chemical messengers across the cell membrane of nerve axons and glial cells.

Teixobactin is a peptide-like secondary metabolite of some species of bacteria, that kills some gram-positive bacteria. It appears to belong to a new class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They are proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

D-Amino acids are amino acids where the stereogenic carbon alpha to the amino group has the D-configuration. For most naturally-occurring amino acids, this carbon has the L-configuration. D-Amino acids are occasionally found in nature as residues in proteins. They are formed from ribosomally-derived D-amino acid residues.

References

  1. 1 2 3 Budavari S (1996). The Merck index: an encyclopedia of chemicals, drugs, and biologicals (12th ed.). Merck. p. 712. ISBN   0911910123. OCLC   34552962.
  2. 1 2 3 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. 1 2 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. 1 2 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. 1 2 3 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. 1 2 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.
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