Gramicidin A
Gramicidin A is a linear 15-amino acid peptide antibiotic from Bacillus brevis that forms cation-selective ion channels in bacterial membranes.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C99H140N20O17 |
| Molecular Weight | 1882.31 g/mol |
| CAS Number | 1405-97-6 |
| IUPAC Name | Val-Gly-Ala-D-Leu-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-D-Leu-Trp |
| Peptide Class | Ion Channel-Forming Antibiotic |
| Origin | Bacillus brevis |
| Composition | Alternating L- and D-amino acids |
Structure
Gramicidin A is a linear pentadecapeptide with alternating L- and D-amino acid residues. This unique stereochemistry enables the peptide to fold into a beta-helix dimer that spans lipid bilayers. The C-terminal ethanolamine and N-terminal formyl group are essential for channel function. Four tryptophan residues (positions 9, 11, 13, 15) anchor the peptide at the membrane-water interface.
Mechanism of Action
Gramicidin A forms ion channels in bacterial membranes:
- Dimerization: Two gramicidin monomers head-to-head form a right-handed beta-helical dimer spanning the lipid bilayer
- Channel formation: The resulting pore (4 Angstrom diameter) is selectively permeable to monovalent cations (H+, K+, Na+)
- Membrane disruption: Uncontrolled cation flux dissipates the membrane potential and osmotic gradient
- Cell death: Loss of ionic homeostasis leads to bacterial cell death
The channel has a single-channel conductance of approximately 20-30 pS and shows exquisite selectivity for monovalent over divalent cations.
Applications
Gramicidin A is primarily used topically:
- Ophthalmic infections: Combined with polymyxin B and neomycin in eye drops (Neosporin)
- Throat infections: Lozenges containing gramicidin for pharyngeal infections
- Skin infections: Topical formulations for superficial bacterial infections
- Research tool: Extensively used to study ion channel biophysics and membrane dynamics
Systemic use is precluded by hemolytic activity and neurotoxicity.
Pharmacokinetics
- Route: Topical application only
- Systemic absorption: Minimal from intact skin/mucosa
- Hemolytic activity: Significant at concentrations above 1 mcg/mL
- Stability: Highly stable due to D-amino acid content and cyclic structure
- Proteolysis: Resistant to most proteases due to alternating D/L stereochemistry
Safety and Side Effects
Gramicidin A is too toxic for systemic use due to hemolytic activity and potential neurotoxicity. Topical use is generally safe at approved concentrations. The D-amino acid content prevents metabolic degradation, contributing to both efficacy and toxicity concerns. Not used intravenously, intramuscularly, or orally for systemic infections.
References
- Andersen, O.S., et al. (2005). Gramicidin channels: molecular models and biological implications. Annual Review of Biophysics, 34, 363-392.
- Kelkar, D.A., & Chattopadhyay, A. (2007). The gramicidin ion channel: a model membrane protein. Biochimica et Biophysica Acta, 1768, 2011-2025.
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