Gramicidines toxicity

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. 

Bacitracin and gramicidin are polypeptide antibiotics with activity against gram-positive organisms and against most anaerobic cocci. Systemic toxicity for bacitracin is rare because of poor absorption through the skin. Gramicidin is used only topically... 

In 1939, Rene Dubos, Waksman s former postdoctoral student, extracted two chemicals, tyrocidine and gramicidin, from the soil germ Bacillus brevis. These chemicals cured bacterial infections in cattle but were too toxic for humans. This discovery prompted a number of scientists to expand the search for microbes in the soil, microbes capable of making chemicals that could kill disease-causing bacteria in humans. 

Gramicidin is available only for topical use, in combination with other antibiotics such as neomycin, polymyxin, bacitracin, and nystatin. Systemic toxicity limits this drug to topical use. The incidence of sensitization following topical application is exceedingly low in therapeutic concentrations. 

There are relatively few chemotherapeutic drugs which cause permeability increases in membranes such as the antifungal polyenes and the antibacterial circular oligopeptides of the tyrocidin, gramicidin and polymyxin families. Most of these are too toxic for systemic use but polymyxins have been given systemically in severe Pseudomonas infections with an attending risk of renal toxicity. 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

The peptides valinomycin (Fig. 10.64) and gramicidin A (Fig. 10.67) both act as ion conducting antibiotics and allow the uncontrolled movement of ions across the cell membrane. Unfortunately, both these agents show no selective toxicity for bacterial over mammalian cells and are therefore useless as therapeutic agents. Their mechanism of action is interesting nevertheless. 

New York) and challenged to find a soil microbe that could destroy a bacteria. ° In 1939, he discovered a substance extracted from a soil bacillns. Tyrothricin (later showed composition of two substances, gramicidin (20%) and tyrocidine (80%), cured mice infected with pnenmococci. It was the first natural antibiotic extracted from soil bacteria, able to arrest the growth of staphylococcns, bnt proved highly toxic. 

Cationic peptides have also been used as DNA carriers. For example, gramicidin S and tyrocidine are cationic peptides that will bind to plasmid DNA. When combined with DOPE, the peptide/DNA complex has been shown to transfect cells in vitro. The efficiency of the peptide compared to liposome/ DNA complexes varies by cell type, but the toxicity is equally low (65). Other types of cationic peptides have also been utilized for gene transfer, and they are most effective in combination with molecules that exhibit pH-dependent membrane perturbation effects (30,66). Presumably these helper components promote endocytic escape after cellular uptake. Cationic peptide-type carriers are not in wide usage at this time, particularly in vivo. It will be interesting to see if these peptides induce any immune response when administered to animals. 

The lipid bilayer of natural membranes presents a complete barrier to the free diffusion of inorganic ions which, being strongly hydrated, lack lipophilicity. However, ionophores are usually on hand to facilitate this transport. There are two kinds of ionophore, the mobile and the stationary. The latter ( ion pumps ) consist of a water-filled channel spanning the bilayer. Much of what we know of ionophores has been learnt from the mobile type, derived from microbes (e.g. valinomycin, gramicidin). Such foreign ionophores, if effective, are toxic to mammalian cells except in low doses. 

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