Peptides, antibiotic structure elucidation

The structure of the uridyl peptide antibiotics was elucidated through extensive NMR studies. These studies assigned the cis geometry of the exocyclic enamide double bond based on an NOE (nuclear Overhauser effect) signal between the vinylic proton and the methylene protons of the amino sugar [271, 272], Boojamra et al. established the absolute stereochemistry of 2,3-diaminobutyric acid as (25,35) [273], while Bugg and coworkers demonstrated the remarkable stability of the enamide present in the uridyl peptide antibiotics [274],... 

Echinomycin (131) has been shown to be an antitumor agent and to have antiviral and antibacterial properties. Its structure elucidation represents a triumph for and mass spectral studies (75JA2497). It has been demonstrated that echinomycin functions by inhibiting RNA synthesis in organisms such as Staphylococcus aureus. Echinomycin, levomycin and actinoleutin are members of the quinoxaline-peptide antibiotic family and all contain one or more quinoxaline rings (67MI21402). 

However, it was not until 1971, when Gross and Morrell reported the structure elucidation of the purified nisin peptide, 12 that it became clear that nisin contained Lan and MeLan residues. Since nisin is an important peptide antibiotic, regularly used in the food production industry as a preservative (preservative EC 234), it has attracted a great deal of attention. Nisin is produced by fermentation, however, partly because of its intriguing structure, it also became the target for the only complete synthesis of a lantibiotic reported to date in the literature. This work has been reviewed. 13 14 ... 

Another example is part of the structural elucidation of 3-hydroxy-5-methyl-2-piperidinecar-boxylic acid, which has been identified as a component of some peptide antibiotics (see p 440). The relative configuration was determined by preparing (unselectively) all four racemic diastereomers 8-11 and subsequent H-NMR and equilibration studies. Thus, 8 and 9 were each converted to an equilibrium mixture of these two isomers in the ratio 2 1 (see p 472). From this experiment it was concluded, that 8 and 9 are epimeric at C-2, and that the more stable isomer has the 2,3-trans configuration 8 (the latter conclusion was based on previous results). In the same way the relative configuration at C-2 and C-3 of 10 and 11 was established274. 

In 1970 Payne et al. 226) elucidated the lipophilic a-helical structure of the eicosapeptide alamethicin 97 (eight a-aminobutyric acid residues = Aib, L-phenylalaninol = Phi), isolated from the culture liquid of the fungus Trichoderma viride. The sequence of the amphiphilic peptide antibiotic was confirmed in 1985 by Jung et al. 227) by total syntheses. 

The prototypical lantibiotic, nisin, was discovered in 1928 for its antibacterial properties and has been used as a preservative in dairy products since the 1950s (1). Nisin and other lantibiotics exhibit nanomolar efficacy against many Gram-positive strains of bacteria (2), which include methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci, and oxacillin resistant bacteria. On the other hand, some lantibiotics function as morphogenetic peptides rather than antibiotics and are important for spore formation in streptomycetes (3). Since the structural elucidation of nisin in the early 1970s, extensive research efforts have been directed at understanding the biosynthesis and mode of action of various lantibiotics. 

Pyrolysis of simple peptides offers models for understanding the pyrolysis results of larger polypeptides and proteins. Also, special types of peptides of practical interest are those with antibiotic properties such as the actinomycins containing peptide side-chains, etc. Their pyrolysis has been proven to be useful for structure elucidation and identification [9]. Other polypeptides with therapeutic use such as lypressin and felypressin were also studied by pyrolysis [10]. 

First, many of these antibiotics, after their discovery, characterization and evaluation, were not of sufficient practical importance and work on them was discontinued. Second, they have relatively complicated structures. Unlike the peptide hormones, which are composed of a limited number of natural amino acids found in proteins, many peptide antibiotics contain a large variety of components other than amino acids. Besides the frequently occurring amino acids not isolated from proteins Table 1.1), many other components, such as hydroxy acids, amino sugars, fatty acids, pyrimidine derivatives and so on, are present Table 1.2). They also often contain unusual peptide linkages, unknown in proteins. Furthermore, most of the peptide antibiotics are of cyclic nature and for this reason are resistant to enzymatic attack, which makes their structural elucidation in many instances more complicated. 

Debono M. Barnhart M. Canell CB, Hoffman JA, Occolowitt JL, Abbott BJ, Fukiula Hamill RL. A21978C, a complex of new acidic peptide antibiotics Isolation, chemistry, and mass spectral structure elucidation, j Antibiot 1987 40 761-777. 

Debono, M., M. Barnhart, C.B. Carrell, J.A. Hoffmann, J.L. Occolowitz, B.J. Abbott, D.S. Fukuda, R.L. Hamil, K. Biemann, and W.C. Herlihy A21978C, a Complex of New Acidic Peptide Antibiotics Isolation, Chemistry and Mass Spectral Structure Elucidation. J. Antibiotics 40, 761 (1987). 

Aydin, M., N. Lucht, W. a. Konig, R. Lupp, G. Jung, and G. Winkelmann Structure Elucidation of the Peptide Antibiotics Herbicolin A and B. Liebigs Ann. Chem. 2285 (1985). 

The structures of tallysomycins A and B, a new antitumor antibiotic complex related to bleomycin, were determined by Konishi et al. 467). The structures of the peptide antibiotic components of thiopeptin containing DH-Ala and DH-Cys units were elucidated 494) and nitrogen-15 n.m.r. investigations gave evidence for the structural relationship between thiostrepton and siomycin-A 495). 

Nucleocidin (LXXX) [353], an adenine nucleoside antibiotic whose structure has recently been elucidated, is also a potent inhibitor of protein synthesis. Studies with this compouna have led to the conclusion that nucleocidin forms a complex with ribosomes which is inactive in peptide bond formation. Binding... 

Peptidelike macrocyclic antibiotics of dimeric and trimeric form are often found, an example being echinomycin A (quinomycin A) produced by Streptomyces echinatus from the soil of Cuanza (Angola). The complete structure of a large peptide macrocycle bearing two 2-quinoxalinyl substituents has been elucidated by Prelog and co-workers.183... 

The elucidation of the structure of telomycin, a macrocyclic peptide lactone, discloses the presence of three novel amino acids, erythro-3-hydroxyleucine, cis- and trans-3-hydroxy-proline the unusual chromophore in this antibiotic (X max 339 mp e = 22,000) is another example of a dehydroamino acid (dehydrotryptophan) unit (XIl). 

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