Tyrothricin

From the biogenetic viewpoint, the tyrothricins are interesting because they contain, unlike the other antibiotic families, two different types of peptides on the one hand the cyclic tyrocidines, and on the other the linear gramicidins A, B, C and D, which are also protected on the amino end by the unusual formyl group and by an ethanolamine residue on the carboxyl end. The latter are the only non-cyclic antibiotics known to the present day Table 1.4). 

Gramicidin S is closely related to the tyrocidines since it contains one of the pentapeptide sequences of tyrocidine repeated twice in its cyclic molecule. 

In 1939 Dubos reported the isolation of the antibiotic tyrothricin from culture filtrates of strains of Bacillus brevis He and his co-workers soon succeeded in separating tyrothricin with organic solvents into two crystalline compounds, the neutral gramicidin and the basic tyrocidine (formerly called graminic acid and gramidinic acid). Tyrothricin is thus a term for the partially purified antibiotic obtained from the culture fluids of Bacillus brevis. It contains on the average a mixture of 20 per cent gramicidin and 80 per cent tyrocidine. Besides these, at least three further polypeptides have been found by countercurrent distribution of tyrothricin. 

The molecular weight of tyrocidine A was found to be about 1,270 . Total hydrolysis and quantitative amino acid analysis revealed the exact composition . Partial hydrolysis, fractionation of the resulting peptide mixture by countercurrent distribution, ion-exchange chromatography and paper-chromatography, followed by sequential analysis, led Paladini and Craig to the structure of tyrocidine A see Table 1.6). 

The structure of the crystalline tyrocidine B was elucidated shortly afterwards in a series of analogous experiments by King and Craig . The only 

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Although tyrothricia is too toxic for parenteral therapy, it was formerly sold in the United States as oral lo2enges. Modem tyrothricin formulations are composed of 70—80% tyrocidines and 30—20% linear gramicidins. Tyrocidines are not as active as linear gramicidins and are too toxic for any therapeutic use by themselves. The bactericidal linear gramicidins are used in the United States solely as an ophthalmic solution in combination with polymyxin B sulfate and neomycin sulfate. The linear gramicidin is used in this aqueous product as a substitute for bacitracin, which lacks stabiUty under such conditions. 

Tyrocidine [8011-61-8] is a mixture of three closely related components. Tyrocidine studies on mechanism of action (98), biosynthesis on multien2yme complexes (93,99,100), and chemistry (101) are available, and tyrothricin production is discussed (102). Although the mechanism of action of linear gramicidins has been well researched, such work on tyrocidine is more limited it appears that tyrocidine damages membranes (103,104). 

Gramicidin is a peptide antibiotic first isolated by Dubos in 19391 as a crude complex together with a second peptide antibiotic known as tyrocidin. The mixture of the two antibiotics was called tyrothricin. Although the mixture was discovered about ten years after penicillin2, tyrothricin was the first antibiotic utilized in clinical practice. 

It was soon found that tyrothricin causes severe hemolysis when administered parenterally and was destroyed when given orally. The antibiotic complex or individual components are effective topically and are used in various cream, ointment, lotion and solution preparations alone or in combination with other antibiotics or topical steroids3. 

Tyrothricin was obtained by acidification of the fermentation broth of Bacillus brevis to precipitate the antibiotic activity along with various proteins and then dissolving the antibiotic complex in alcohol. The alcohol was removed under vacuum, the residue was washed with ether, then redissolved in alcohol and finally reprecipitated with 1% sodium chloride5 6. 

It was soon recognized that tyrothricin was not a pure compound but could be separated into a neutral fraction called gramicidin and a basic fraction called tyroci-... 

A number of reports have indicated that tyrothricin is more soluble in solutions of quaternary ammonium compounds56 60. 

When it was realized that tyrothricin was a mixture of antibiotics, the same principle was applied to gramicidin 62 65 64 65. The addition of quaternary pounds to gramicidin formulations to increase the solubility of the antibiotic in aqueous solution has been utilized66 67. 

The gramicidin complex was originally isolated by Dubos as a component of the antibiotic mixture called tyrothricin formed by an aerobic sporulating bacillus7. 

A number of workers have described the production of tyrothricin in a synthetic medium supplemented with organic nitrogen compounds96 97f98r99/100. 

Rittenberg and coworkers used a colorimetric assay for tryptophane to determine tyrothricin in fermentation broth152. Kreuzig described a semi-automated colorimetric assay for gramicidin utilizing the reaction of... 

In the following sections, polymyxins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use. 

Sprays are preparation of drugs in oil or water, usually administered by atomizer or nebulizer. They are applied to the mucosae of nose or throat e.g. Tyrothricin spray. 

Tyrothricin (0.5 mg/kg skin cream, 0.2 mg/ml solution (topical), 0.05% as otic solution with benzocaine... 

In the following sections, plasmalemmadamaging polymyxins and tyrothricin are Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

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