Tyrothricin
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Identification
- Summary
Tyrothricin is a topical antibiotic with broad spectrum activity against Gram positive bacteria and some fungal infections.
- Generic Name
- Tyrothricin
- DrugBank Accession Number
- DB13503
- Background
Tyrothricin is an antibiotic peptide complex produced and extracted from the aerobic Gram-positive bacillus Brevibacillus parabrevis 11,12,2 which was previously categorized as Bacillus brevis and Bacillus aneurinolyticus 9. This complex is a mixture comprised of 60% tyrocidine cationic cyclic decapeptides (consisting largely of the six predominant tyrocidines, TrcA/A1, TrcB/B1, TrcC/C1, and other more minor contributors) and 40% neutral linear gramicidins (where valine-gramicidin A is often the major gramicidin present, although the mixture composition can vary) 11,12,13. Moreover, tyrothricin possesses broad spectrum Gram-positive antibacterial and antifungal activity that has not seen many - if any - significant reportings of microbial resistance during the over 60 years of therapeutic use the complex has provided 10. Nevertheless, as tyrothricin is both cytolytic and hemolytic, it does demonstrate systemic toxicity 11,12,13, although certain formulations that are safe for human use like throat lozenges do exist 14.
- Type
- Small Molecule
- Groups
- Approved
- Synonyms
- Bactratycin
- Hydrotricine
- Tirotricina
- Tyrothricin
- Tyrothricine
- Tyrothricinum
Pharmacology
- Indication
Tyrothricin is used as an over the counter topical antibiotic.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Bacterial sinusitis Combination Product in combination with: Naphazoline (DB06711) •••••••••••• Treatment of Bacterial sinusitis •••••••••••• •••••••• • ••••• Used in combination to treat Bacterial rhinitis Combination Product in combination with: Naphazoline (DB06711) •••••••••••• Treatment of Bacterial rhinitis •••••••••••• •••••••• • ••••• Used in combination to treat Gingivitis Combination Product in combination with: Benzocaine (DB01086) •••••••••••• ••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Tyrothricin consists of a mix of tyrocidines and gramcidins which exert a bacteriocidal effect. This clears the area of pathogenic bacteria to allow the body to heal wounds or other damage to the skin.
- Mechanism of action
Tyrocidines have a β-sheet structure containing both L and D amino acids 3. These structural features contribute to the formation of a curved dimer in which most amino acid side chains are located on the convex surface. The dimer orients itself at the membrane-water interface on bacterial cells with the relatively hydrophilic back-bone on the concave side facing the external environment and the many hydrophobic side chains on the convex side facing into the cell's lipid bilayer. The tyrocidine dimer is able to disrupt the cell membrane producing leakage of cell contents but the exact mechanism of this permeabilization is unclear.
Tyrocidines appear to act as reversible non-competitive inhibitors of acetylcholinesterase and β-galactosidase 4. The relation of this to their antibacterial action is unknown.
Gramcidins adopt similar β-sheet structures but are capable of forming β-helices 5. They can either form a double helix, running either parallel or anti-parallel, or a helical dimer wherein the N-termini of each polypeptide meets in the middle of the lipid bilayer. The alternating L and D amino acid structure allows the hydrophobic side chains to point outwards into the lipid bilayer, leaving the more hydrophilic backbone to form the lumen of the pore. The carbonyl oxygen atoms aid in the transport of cations through the pore. In both double helix and helical dimer conformations, gramcidins are capable of transporting monovalent cations through the membrane. Divalent cations result in blockage of the pore or channel when bound. Loss of potassium ions through membrane permeabilization seems to inhibit bacterial growth.
Gramcidin also appears to be able to insert into the mitochondial membrane and conduct hydrogen ions 6. This results in an uncoupling of oxidative phosphorylation from ATP generation due to the loss of the hydrogen ion gradient necessary for H+ATPase function.
Target Actions Organism APhospholipid membrane disruptorEscherichia coli (strain K12) UAcetylcholinesterase inhibitorHumans UBeta-galactosidase inhibitorEscherichia coli (strain K12) - Absorption
The lack of water solubility prevents absorption of tyrothricin through the skin. It is not used through other routes due to toxicity concerns 1.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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- Toxicity
The components of tyrothricin are capable of disrupting eukaryotic cell membranes at high concentrations resulting in toxicity 8. This manifests as hemolysis in systemic administration. It is thought that the cholesterol present in eukaryotic cells affords some resistance to the toxic mechanisms of tyrothricin 7. Loss of olfactory function has been noted and topical administration to the nasal mucous membranes is not recommended 1.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcebutolol Tyrothricin may increase the bradycardic activities of Acebutolol. Acenocoumarol The risk or severity of bleeding can be increased when Tyrothricin is combined with Acenocoumarol. Acetylcholine The risk or severity of adverse effects can be increased when Tyrothricin is combined with Acetylcholine. Aclidinium Tyrothricin may increase the neuromuscular blocking activities of Aclidinium. Amantadine The therapeutic efficacy of Amantadine can be decreased when used in combination with Tyrothricin. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Antibiotic Cold Sore Ointment Tyrothricin (0.5 mg / g) + Benzocaine (50 mg / g) + Camphor (20 mg / g) + Levomenthol (1 mg / g) + Polymyxin B (500 unit / g) Ointment Topical Columbia Laboratories 1992-12-31 2009-07-17 Canada Antibiotic Lozenges Tyrothricin (1.5 mg / loz) + Benzocaine (5.0 mg / loz) + Cetylpyridinium chloride (1.3 mg / loz) + Polymyxin B sulfate (1500 unit / loz) Lozenge Oral Nutribon (1986) Inc. 1994-12-31 2003-07-25 Canada BEATHRICIN LOZENGES Tyrothricin (1 mg) + Lidocaine (5 mg) Lozenge Oral BEACONS PHARMACEUTICALS PTE. LTD. 1994-12-31 Not applicable Singapore DELTAVAGIN Tyrothricin (10 mg) + Betamethasone (2 mg) + Norvaline (100 mg) Insert Vaginal Farmitalia Industria Chimico Farmaceutica S.R.L. 2014-07-08 2022-02-16 Italy DELTAVAGIN Tyrothricin (10 mg) + Betamethasone (2 mg) + Norvaline (100 mg) Insert Vaginal Farmitalia Industria Chimico Farmaceutica S.R.L. 2014-07-08 Not applicable Italy
Categories
- ATC Codes
- S01AA05 — TyrothricinR02AB02 — TyrothricinD06AX08 — Tyrothricin
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 877376V2XW
- CAS number
- 1404-88-2
References
- Synthesis Reference
Vosloo JA, Stander MA, Leussa AN, Spathelf BM, Rautenbach M. Manipulation of the tyrothricin production profile of Bacillus aneurinolyticus. Microbiology (Reading, Engl). 2013;159(Pt 10):2200-11.
- General References
- Lang C, Staiger C: Tyrothricin--An underrated agent for the treatment of bacterial skin infections and superficial wounds? Pharmazie. 2016 Jun;71(6):299-305. [Article]
- Vosloo JA, Stander MA, Leussa AN, Spathelf BM, Rautenbach M: Manipulation of the tyrothricin production profile of Bacillus aneurinolyticus. Microbiology. 2013 Oct;159(Pt 10):2200-11. doi: 10.1099/mic.0.068734-0. Epub 2013 Aug 20. [Article]
- Loll PJ, Upton EC, Nahoum V, Economou NJ, Cocklin S: The high resolution structure of tyrocidine A reveals an amphipathic dimer. Biochim Biophys Acta. 2014 May;1838(5):1199-207. doi: 10.1016/j.bbamem.2014.01.033. Epub 2014 Feb 11. [Article]
- Changeux JP, Ryter A, Leuzinger W, Barrand P, Podleski T: On the association of tyrocidine with acetylcholinesterase. Proc Natl Acad Sci U S A. 1969 Mar;62(3):986-93. [Article]
- Wallace BA: Recent Advances in the High Resolution Structures of Bacterial Channels: Gramicidin A. J Struct Biol. 1998;121(2):123-41. doi: 10.1006/jsbi.1997.3948. [Article]
- Sorochkina AI, Plotnikov EY, Rokitskaya TI, Kovalchuk SI, Kotova EA, Sychev SV, Zorov DB, Antonenko YN: N-terminally glutamate-substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler. PLoS One. 2012;7(7):e41919. doi: 10.1371/journal.pone.0041919. Epub 2012 Jul 24. [Article]
- Prenner EJ, Lewis RN, Jelokhani-Niaraki M, Hodges RS, McElhaney RN: Cholesterol attenuates the interaction of the antimicrobial peptide gramicidin S with phospholipid bilayer membranes. Biochim Biophys Acta. 2001 Feb 9;1510(1-2):83-92. [Article]
- Qin C, Zhong X, Bu X, Ng NL, Guo Z: Dissociation of antibacterial and hemolytic activities of an amphipathic peptide antibiotic. J Med Chem. 2003 Nov 6;46(23):4830-3. doi: 10.1021/jm0341352. [Article]
- Shida O, Takagi H, Kadowaki K, Komagata K: Proposal for two new genera, Brevibacillus gen. nov. and Aneurinibacillus gen. nov. Int J Syst Bacteriol. 1996 Oct;46(4):939-46. doi: 10.1099/00207713-46-4-939. [Article]
- Stauss-Grabo M, Atiye S, Le T, Kretschmar M: Decade-long use of the antimicrobial peptide combination tyrothricin does not pose a major risk of acquired resistance with gram-positive bacteria and Candida spp. Pharmazie. 2014 Nov;69(11):838-41. [Article]
- Arnold Vosloo, J., Beims, H., Allsopp, M.H. et al. Tolerance of honey bee adults and larvae toward tyrothricin peptides derived from Brevibacillus parabrevis Apidologie (2017) 48: 833. https://doi.org/10.1007/s13592-017-0528-0 [Link]
- National Research Foundation Institutional Repository: Characterization of natural antimicrobial peptides adsorbed to different matrices [Link]
- Production and characterisation of analogues of the antimicrobial tyrocidine peptides with modified aromatic amino acid residues. [Link]
- Electronic Medicines Compendium: Tyrozets (benzocaine and tyrothricin) lozenges Monograph [Link]
- External Links
- ChemSpider
- 398608
- 10968
- ChEMBL
- CHEMBL577736
- Wikipedia
- Tyrothricin
- MSDS
- Download (320 KB)
Clinical Trials
- Clinical Trials
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Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Ointment Topical Lozenge Oral 5 mg Insert Vaginal Tablet Oral 0.25 mg Tablet, orally disintegrating Suppository Vaginal Spray Transmucosal Tablet Lozenge Oral 1 mg Lozenge Buccal Solution / drops Nasal Solution / drops Nasal 0.25 mg/ml Lozenge Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble Lang C, Staiger C. Tyrothricin--An underrated agent for the treatment of bacterial skin infections and superficial wounds?. Pharmazie. 2016;71(6):299-305. - Predicted Properties
- Not Available
- Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
References
- Lang C, Staiger C: Tyrothricin--An underrated agent for the treatment of bacterial skin infections and superficial wounds? Pharmazie. 2016 Jun;71(6):299-305. [Article]
- Loll PJ, Upton EC, Nahoum V, Economou NJ, Cocklin S: The high resolution structure of tyrocidine A reveals an amphipathic dimer. Biochim Biophys Acta. 2014 May;1838(5):1199-207. doi: 10.1016/j.bbamem.2014.01.033. Epub 2014 Feb 11. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Non-competitive inhibitor. Maximum inhibition found to be 60% of enzyme activity.
- General Function
- Hydrolyzes rapidly the acetylcholine neurotransmitter released into the synaptic cleft allowing to terminate the signal transduction at the neuromuscular junction. Role in neuronal apoptosis
- Specific Function
- acetylcholine binding
- Gene Name
- ACHE
- Uniprot ID
- P22303
- Uniprot Name
- Acetylcholinesterase
- Molecular Weight
- 67795.525 Da
References
- Changeux JP, Ryter A, Leuzinger W, Barrand P, Podleski T: On the association of tyrocidine with acetylcholinesterase. Proc Natl Acad Sci U S A. 1969 Mar;62(3):986-93. [Article]
- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Very weak inhibition.
- General Function
- Not Available
- Specific Function
- alkali metal ion binding
- Gene Name
- lacZ
- Uniprot ID
- P00722
- Uniprot Name
- Beta-galactosidase
- Molecular Weight
- 116482.045 Da
References
- Changeux JP, Ryter A, Leuzinger W, Barrand P, Podleski T: On the association of tyrocidine with acetylcholinesterase. Proc Natl Acad Sci U S A. 1969 Mar;62(3):986-93. [Article]
Drug created at June 23, 2017 20:43 / Updated at May 29, 2021 18:11