1405-97-6

Usage

Uses

Used in Medicine (Antibacterial):
Gramicidin is used as a topical antimicrobial agent, particularly effective against Gram-positive bacteria. It is commonly used in the treatment of bacterial skin infections due to its ability to inhibit bacterial growth by forming channels in the cell membrane, causing ion leakage.
Used in Research:
Gramicidin serves as an essential bioprobe for understanding the nature of cell membranes. Its ionophore properties, which allow it to form channels in bacterial cell membranes, make it a valuable tool in studying membrane permeability and ion transport.
Used in Combination with Other Antibiotics:
Gramicidin is available in various topical preparations containing other antibiotics, such as bacitracin and neomycin. These combinations enhance the overall effectiveness of the treatment against a broader range of bacterial infections.
Used in Branded Products:
Gramicidin is marketed under the brand name Gramoderm (Schering) and is used in pharmaceutical formulations for its antimicrobial properties.
Chemical Properties:
Gramicidin is characterized by its white, crystalline platelet appearance. It is soluble in lower alcohols, acetic acid, and pyridine, moderately soluble in dry acetone and dioxane, and almost insoluble in water, ether, and hydrocarbons. It has the ability to depress surface tension and form a fairly stable colloidal emulsion in distilled water.

Antimicrobial activity

Gramicidin is highly active against many Gram-positive bacteria. Neisseria spp. are relatively resistant. Gram-negative bacilli including Pseudomonas aeruginosa are susceptible although conflicting data exist about the degree of susceptibility. Gramicidin has a bactericidal activity against Mycoplasma spp. and several pathogenic fungi, including Candida albicans. Interestingly, it also appears to have antiviral activity against HIV and herpes simplex viruses (HSV-1, HSV-2).

Pharmaceutical Applications

Gramicidin as used in topical formulations is a mixture of several closely related compounds, of which about 80% is in the form of gramicidin A. It is part of the tyrothricin complex originally isolated from B. brevis. It is active against most species of Gram-positive bacteria, including mycobacteria. Gram-negative bacilli are completely insensitive. It is highly toxic to erythrocytes, liver and kidney, and is used only in topical formulations, usually as one of several components.

Biochem/physiol Actions

Linear polypeptide antibiotic mixture of gramicidin A, B, C, and D. Gramicidin A acts as neutral carrier and helps in the establishment of ion flux across the lipid bilayer.

Mechanism of action

The mechanisms of gramicidin’s bactericidal activity have not been fully elucidated. Gramicidin is known to alter the function of the bacterial cytoplasmic membrane by forming channels that destroy the ion gradient and make it permeable for inorganic cations . It may also be a potent and specific inhibitor of the transcription reaction and inhibit the binding of DNA-dependent RNA polymerase (transcriptase) to DNA . Gramicidin appears to have antiviral activity against HIV, HSV-1, and HSV-2 viruses and is also used as a contraceptive due to its spermostatic properties.

Clinical Use

The use of gramicidin is restricted to topical applications on wounds or as ear and eye drops. Currently, much research is being invested to generate less toxic analogs that still exhibit the same wide range of bactericidal activity. To date, no new gramicidin-like polypeptides are available for clinical use. Gramicidin is used in some countries as a topical contraceptive, because it has spermostatic activity.

InChI: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)

Synthetic route

C119H172N20O25 → Gramicidin A (1405-97-6)

Conditions	Yield
With chlorotriisopropylsilane; water; trifluoroacetic acid; phenol In dichloromethane at 25℃; for 1h; Inert atmosphere;

C117H166N19O24Pol + ethanolamine (141-43-5) → Gramicidin A (1405-97-6)

Conditions	Yield
Stage #1: C117H166N19O24Pol With trifluoroacetic acid In water at 20℃; hydroxymethylbenzoic acid-TentaGel macrobeads; Stage #2: ethanolamine In N,N-dimethyl-formamide at 50℃; hydroxymethylbenzoic acid-TentaGel macrobeads;

Gramicidin A (1405-97-6) → C99(2)H140N20O17

Conditions	Yield
With deuteromethanol for 24h;

Upstream product

• 141-43-5 ethanolamine 

Relevant academic research and scientific papers

Polar groups in membrane channels: Consequences of replacing alanines with serines in membrane-spanning gramicidin channels

To explore the consequences of burying polar, hydrogen-bonding hydroxyl groups within the hydrocarbon core of lipid bilayer membranes, we examined the structural and functional effects of alanine-to-serine substitutions in bilayer-spanning gramicidin channels. A native Ala was replaced by Ser at position 3 or 5 in the gramicidin A (gA) sequence: formyl-VG2A 3LA5VVVWLWLWLW-ethanolamide (d-residues underlined). In the head-to-head dimers that form the conducting, membrane-spanning gA channels, these sequence positions are located near the lipid bilayer center (and subunit interface). The sequence substitutions at positions 3 and 5 were tested within the context of having either Gly or d-Ala at position 2, because d-Ala 2 causes the channel lifetimes to increase 3-fold relative to Gly2 [Mattice et al. (1995) Biochemistry 34, 6827]. Size-exclusion chromatograms and circular dichroism spectra show that the Ala → Ser replacements are well tolerated and have little effect on channel structure. In planar bilayers, the Ser-substituted gramicidins form well-defined channels, with cation conductances that are ～60% of those of the reference channels. The Ser-substituted channels are structurally equivalent to native gramicidin channels, as demonstrated by the formation of heterodimeric channels between a Ser-containing subunit and a native gramicidin subunit. These hybrid channels exhibit rectification, attributable to asymmetric placement of the single Ser hydroxyl group with respect to the bilayer center. Compared to the corresponding Ala-containing reference channels, the polar Ser residues decrease the analogues channel-forming potency by 3 orders of magnitude, indicating a substantial energetic penalty (～15 kJ/mol) for burying the polar Ser side chain in the bilayer hydrophobic core.

Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.