Identification

Name
Tyrothricin
Accession Number
DB13503
Type
Small Molecule
Groups
Approved
Description

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].

Synonyms
  • Bactratycin
  • Hydrotricine
  • Tirotricina
  • Tyrothricine
  • Tyrothricinum
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Antibiotic Cold Sore OintmentTyrothricin (0.5 mg) + Benzocaine (50 mg) + Camphor (20 mg) + Menthol (1 mg) + Polymyxin B Sulfate (500 unit)OintmentTopicalColumbia Laboratories1992-12-312009-07-17Canada
Antibiotic LozengesTyrothricin (1.5 mg) + Benzocaine (5.0 mg) + Cetylpyridinium chloride (1.3 mg) + Polymyxin B Sulfate (1500 unit)LozengeOralNutribon (1986) Inc.1994-12-312003-07-25Canada
Emercreme No4 Ont EfaTyrothricin (1 mg) + Bacitracin (65 unit) + Benzocaine (20 mg) + Cetylpyridinium chloride (.4 mg) + Diphenylpyraline hydrochloride (2 mg)OintmentTopicalPharmavite Laboratories (1987) Inc.1984-12-31Not applicableCanada
GercillinTyrothricin (1.5 mg) + Bacitracin (1 mg) + Benzocaine (5 mg) + Polymyxin B Sulfate (1500 unit)LozengeOralLes Produits Gerbex Inc.1987-12-312004-09-23Canada
Laryngets LozTyrothricin (1.5 mg) + Benzocaine (5 mg) + Cetylpyridinium chloride (1.3 mg) + Polymyxin B Sulfate (1500 unit)LozengeBuccalNutribon (1986) Inc.1992-12-312003-07-25Canada
Pulmosirum PastilleTyrothricin (1.5 mg) + Benzocaine (5 mg) + Cetylpyridinium chloride (1.3 mg) + Polymyxin B Sulfate (1500 unit)LozengeOralNutribon (1986) Inc.1994-12-312003-07-25Canada
Categories
UNII
877376V2XW
CAS number
1404-88-2
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

Tyrothricin is used as an over the counter topical antibiotic.

Associated Conditions
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.

TargetActionsOrganism
UAcetylcholinesterase
inhibitor
Human
UBeta-galactosidase
inhibitor
Escherichia coli (strain K12)
APhospholipid membrane
disruptor
Escherichia 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
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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Tyrothricin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Tyrothricin is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Tyrothricin is combined with 4-hydroxycoumarin.
AcebutololTyrothricin may increase the bradycardic activities of Acebutolol.
AcenocoumarolThe risk or severity of bleeding can be increased when Tyrothricin is combined with Acenocoumarol.
AcetylcholineThe risk or severity of adverse effects can be increased when Tyrothricin is combined with Acetylcholine.
AclidiniumThe therapeutic efficacy of Aclidinium can be decreased when used in combination with Tyrothricin.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Tyrothricin.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Tyrothricin.
AlcuroniumThe therapeutic efficacy of Alcuronium can be decreased when used in combination with Tyrothricin.
Food Interactions
Not Available

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
  1. 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. [PubMed:27455547]
  2. 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. [PubMed:23963303]
  3. 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. [PubMed:24530898]
  4. 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. [PubMed:5257018]
  5. 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. [PubMed:9618340]
  6. 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. [PubMed:22911866]
  7. 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. [PubMed:11342149]
  8. 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. [PubMed:14584933]
  9. 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. [PubMed:8863420]
  10. 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. [PubMed:25985581]
  11. 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]
  12. National Research Foundation Institutional Repository: Characterization of natural antimicrobial peptides adsorbed to different matrices [Link]
  13. Production and characterisation of analogues of the antimicrobial tyrocidine peptides with modified aromatic amino acid residues. [Link]
  14. Electronic Medicines Compendium: Tyrozets (benzocaine and tyrothricin) lozenges Monograph [Link]
External Links
ChemSpider
398608
ChEMBL
CHEMBL577736
Wikipedia
Tyrothricin
ATC Codes
R02AB02 — TyrothricinD06AX08 — TyrothricinS01AA05 — Tyrothricin
MSDS
Download (320 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
OintmentTopical
LozengeBuccal
LozengeOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleLang 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

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Non-competitive inhibitor. Maximum inhibition found to be 60% of enzyme activity.
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
References
  1. 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. [PubMed:5257018]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Very weak inhibition.
General Function
Magnesium ion binding
Specific Function
Not Available
Gene Name
lacZ
Uniprot ID
P00722
Uniprot Name
Beta-galactosidase
Molecular Weight
116482.045 Da
References
  1. 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. [PubMed:5257018]
3. Phospholipid membrane
Kind
Group
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Disruptor
References
  1. 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. [PubMed:27455547]
  2. 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. [PubMed:24530898]

Drug created on June 23, 2017 14:43 / Updated on November 02, 2018 07:41