Gramicidin S Antibiotic

Beta structures are found in many small peptides. Tire hormone oxytocin (Fig. 2-4), the antibiotics gramicidin S (Fig. 2-4) and valinomycin (Fig. 8-22), and the mushroom peptide antamanide (Box 28-B) are among these. The cyclic structures of these compounds favor formation of antiparallel (3 strands with sharp turns at the ends. Polypeptide antibiotics that have alternating... 

Ripka et al.[167 168l suggested that benzodiazepines of the type 138 (Scheme 52, experimental details given below) could serve as a mimetic of a (3-turn. This mimetic was incorporated into a cyclic octapeptide -containing analogue of the antibiotic peptide gramicidin S to provide 139 (Scheme 53). 

CNMR investigations of several cyclic and acyclic peptide antibiotics and toxins have been reported in the literature, e.g., gramicidin S-A (cyclo(Phe-Pro-Val-Orn-Leu)2) [176, 801, 872 875], viomycin (cyclopeptide constituted of L-serine, at, I-L-di-aminopropionic acid, /J-L-lysine and viomycidine) [876], bacitracin A (Ile-Cys-Leu-D-Glu-Ile-Lys-n-Orn-Ile) [815], alamethicin (Ac-Aib-Pro-Val-Aib-Val-Aib-Aib-Ala-Aib-... 

Among the peptide antibiotics are gramicidin S (from Bacillus brevis) and bacitracin A (from Bacillus subtilis), which contain D-amino acids in addition to l-amino acids ... 

Gramicidin S is a cyclic decapeptide antibiotic with the following sequence ... 

Given the limitations of the above systems, it is apparent that the optimal peptide model of a p-sheet (and a p-turn) should be as analagous to the monomeric helix models as possible. In particular, the ideal p-sheet model should be small (< 20 residues), monomeric, water-soluble, pure (composed of only p-sheets and p-turns), amphipathic (to investigate sidedness), reversibly denaturable, composed of only natural amino acids, easily synthesized and easily characterized by standard spectroscopic techniques. We believe that we have developed such a peptide model. It is based on the naturally occurring cyclic peptide gramicidin S, an antibiotic produced by the bacterium bacillus brevis (12). The schematic structure of gramicidin S as determined by X-ray and NMR studies (13, 14) is shown in Figure 1. 

GR 159897 is an indolylpiperidine, a TACHYKININ RECEPTOR ANTAGONIST selective for the NK -receptor subtype. It shows ANXIOLYTIC properties in animal models, gramicidin S [inn] is a (cyclic peptide) antibiotic. Active as an antibacterial and used clinically topically against Gram-positive bacteria. 

The majority of these substances may be considered unique polypeptides which contain unusual amino acids or amino acids joined in some unusual manner. Antibiotics now definitely known to be in this class are the penicillins (2), gramicidin (2), tyrocidine (1), gramicidin-S 3), bacitracin (4), subtilin (-5), polymyxin (6), aerosporin (7) and others. The penicillins are produced by a mold. The others listed here are produced by related bacteria. Streptomycin is a very important antibiotic therapeutically but it does not belong to the polypeptide class, being a complex amino-sugar derivative. 

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. 

Even in the case it should be possible to separate ribozyme activity from the ribosome or to isolate an in vitro selected ribozyme that can catalyze the same type of peptide bond formation as a ribosome, however such a biocatalyst seem does not to be suitable for simple practical use rather than using a chemical coupling reagent. In principle, this conclusion is also valid for the nonribosomal poly- or multienzymes which are involved in the biosynthesis of peptide antibiotics[7Z. Up to now, they have only found application in the synthesis field of cyclosporin, gramicidin S, special P-lactam antibiotics and analogs. 

Despite the apparent connections between formation of antibiotics and spores, it has become clear that antibiotic production is not obligatory for spore formation [192]. The most damaging evidence to the antibiotic-spore obligatory hypothesis is the existence of mutants which form no antibiotic but still sporulate. Such mutants have been found in the cases of bacitracin (Bacillus licheniformis), myco-bacillin (Bacillus subtilis), linear gramicidin (B. brevis), tyrocidine (B. brevis), gramicidin S (B. brevis), oxytetracycline (Streptomyces rimosus), streptomycin (S. griseus), methylenomycin A (Streptomyces coelicolor), and patulin (Penicillium urticae). 

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