Tyrothricin

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Structural formula
Structural formula of tyrocidin A
Structural formula of the component tyrocidin A
General
Non-proprietary name Tyrothricin
Molecular formula see. table
External identifiers / databases
CAS number 1404-88-2
EC number 215-771-0
ECHA InfoCard 100.014.337
PubChem 452550
Wikidata Q419421
Drug information
ATC code
Drug class

Antibiotics

properties
Molar mass see. table
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data

> 3000 mg kg −1 ( LD 50mouseoral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tyrothricin is a mixture of various antibacterially effective linear and cyclic polypeptides from the groups of gramicidins and tyrocidins . They are formed endotoxin-like by the anaerobic spore-forming Bacillus aneurinolyticus ( syn . Bacillus brevis ). The range of action mainly includes gram-positive bacteria , but also some gram-negative bacteria and various types of fungi , such as Candida albicans .

Tyrothricin is assigned to the polypeptide antibiotics , which also include actinomycin , bacitracin and the polymyxins .

composition

Tyrothricin contains 50 to 70% tyrocidine and 25 to 50% gramicidine, which together make up at least 85% of the active ingredient. In addition, other structurally related polypeptides occur in small amounts.

Structure of the tyrocidines in tyrothricin
Basic structure
D-Phe- L-Pro- X - Y - L-Asn- L-Gln- Z - L-Val- L-Orn- L-Leu
└─────────────────────────────────── ─────────┘
Tyrocidine Molecular formula molar mass CAS no. X Y Z
A. C 66 H 88 N 13 O 13 1271 1481-70-5 L-Phe D-Phe L-Tyr
B. C 68 H 89 N 14 O 13 1311 865-28-1 L-Trp D-Phe L-Tyr
C. C 70 H 90 N 15 O 13 1350 3252-29-7 L-Trp D-Trp L-Tyr
D. C 72 H 91 N 16 O 12 1373 19716-16-6 L-Trp D-Trp L-Trp
E. C 66 H 88 N 13 O 12 1255 19659-41-7 L-Phe D-Phe L-Phe
Structure of the gramicidins in tyrothricin
Basic structure
HCO- X - Gly- L-Ala- D-Leu- L-Ala- D-Val- L-Val- D-Val- L-Trp–
- D-Leu- Y - D-Leu- L-Trp- D-Leu- L-Trp-NH-CH 2 -CH 2 -OH
Gramicidin Molecular formula molar mass X Y
A1 C 99 H 140 N 20 O 17 1882 L-Val L-Trp
A2 C 100 H 142 N 20 O 17 1896 L-Ile L-Trp
C1 C 97 H 139 N 19 O 18 1859 L-Val L-Tyr
C2 C 98 H 141 N 19 O 18 1873 L-Ile L-Tyr

effect

Bacteriostatic or
bactericidal action against
Inhibitory dose
in μg / ml
Staphylococcus aureus MSSA 04th
Staphylococcus aureus MRSA 04th
Staphylococcus haemolyticus 04th
Streptococcus pyogenes 00.5
Streptococcus viridans 01 - 5
Enterococcus faecalis 02
Diplococcus pneumonia 01
Corynebacterium spp. 02
Clostridia 00.1-10
Candida albicans 16
Candida parapsilosis 32

Tyrothricin is an antimicrobial polypeptide that irreversibly damages the cell membranes of various microorganisms . Its mode of action is very similar to the antimicrobial peptides (or host defense peptides ), as they are known from eukaryotes (e.g. defensin and cathelicidin ). Because of this similarity, they are now increasingly assigned to this group ( non-ribosomally synthesized antimicrobial polypeptides ).

As a mixture of two active substance groups, tyrothricin acts on the microbial cell wall in two ways:

Tyrocidines are deposited in the cell membrane of microorganisms and thus destroy their function. The exact location and mechanism are not yet known.

Gramicidins form cation-selective channels in the cell membrane through which monovalently charged cations (such as potassium, sodium) can pass the membrane. Among other things, the ion gradient between the cytoplasm and the extracellular medium is canceled here.

The development of resistance shows that, despite decades of use, tyrothricin shows an unbroken high level of effectiveness even against Staphylococcus aureus strains with multiple antibiotic resistance ( MRSA ). There is also no cross-resistance with polymyxin B and colistin .

The reason for this sustained effectiveness and failure to develop resistance is suspected to be the direct and double attack on the cell membrane by microorganisms. In order to develop resistance, pathogens would have to change the nature and composition of their cell membranes, a complicated and (in terms of evolution) very time-consuming process.

Because of this consistently high effect, tyrothricin, with its active ingredients gramicidin and tyrocidin, has come under increasing scrutiny in recent years.

In various experiments, other properties of tyrothricin were discovered, for example the activation of the innate, unspecific immune system or the inhibition of the release of the tumor necrosis factor TNF .

application

Tyrothricin is used only locally. In this context, the antibiotic in the form of throat tablets is used for sore throats and sore throats with difficulty swallowing, for throat and larynx infections and for inflammation of the oral mucosa and gums. The peptide is destroyed in the gastrointestinal tract and there is no measurable absorption when applied locally to the skin or mucous membranes.

In addition, tyrothricin is used for the soothing treatment of small, superficial, less exuding wounds of the skin with bacterial superinfection with tyrothricin-sensitive pathogens, such as. B. cracks, scratches, abrasions are used.

Side effects

When used locally, hypersensitivity reactions to the active ingredient such as burning or itching of the skin or mucous membranes have been observed. So far there are no long-term studies on the effects during pregnancy and breastfeeding .

In systemic absorption, it can cause severe nephrotoxic and neurotoxic come side effects.

history

Tyrothricin was discovered in 1939 by the French René Jules Dubos in breeding experiments with soil samples and pneumococci and isolated from culture filtrates of Bacillus brevis . The first brand names were Tyrosolvin (from Byk Gulden ) and Tyrocid (from Grünenthal ).

Trade names

Monopreparations

Tyrosur (D)

Combination preparations

numerous generics (A, CH)

Individual evidence

  1. Data sheet Tyrothricin from Bacillus aneurinolyticus (Bacillus brevis) from Sigma-Aldrich , accessed on May 29, 2011 ( PDF ).
  2. Entry on tyrothricin in the ChemIDplus database of the United States National Library of Medicine (NLM)
  3. ^ European Pharmacopoeia. Edition 8.0, 2015, p. 3502.
  4. ^ Theodor Dingermann et al.: Pharmaceutical Biology - Molecular Basics and Clinical Application. Springer Verlag, Frankfurt / Munich 2002, ISBN 3-540-42844-5 .
  5. a b B. M. Spathelf: Qualitative structure-activity relationships of the major tyrocidines, cyclic decapeptides from Bacillus aneurinolyticus. Dissertation. University of Stellenbosch, 2010, (Chapter 1.4).
  6. M. Kretschmar, W. Witte, H. Hof: Bactericidal activity of tyrothricin against methicillin-resistant Staphylococcus aureus with reduced susceptibility to mupirocin. In: European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. Volume 15, Number 3, March 1996, pp. 261-263. PMID 8740868 .
  7. a b c M. A. Marques, DM Citron, CC Wang: Development of Tyrocidine A analogues with improved antibacterial activity. In: Bioorganic & Medicinal Chemistry . Volume 15, Number 21, November 2007, pp. 6667-6677, doi: 10.1016 / j.bmc.2007.08.007 . PMID 17728134 . PMC 2706120 (free full text).
  8. M. Stauss-Grabo, S. Atiye, T. Le, M. Kretschmar: 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. In: Pharmacy. 69 (11), Nov 2014, pp. 838-841. PMID 25985581 .
  9. M. Flügel: Cationic peptides - more than antibiotics. In: Deutsche Apotheker Zeitung. No. 48, 2013, p. 26.
  10. Package insert Dorithricin throat tablets (PDF; 1.8 MB).
  11. ^ HE Voigt, G. Ehlers: Tyrothricin: Renaissance of a local antibiotic, part I. In: Der Deutsche Dermatologe. 37 (6), 1989, pp. 647-650.
  12. Tyrosur Gel package insert ( Memento from August 13, 2015 in the Internet Archive ) (PDF; 112 kB).
  13. ^ Alfons Metzner: World problem health. Imhausen International Company mbh , Lahr (Black Forest) 1961, p. 237.
  14. Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition, ibid. 1961, pp. 9–223, here: p. 54.
  15. ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, ISBN 978-3-946057-10-9 , p. 224.