Peptides, antibiotic synthesis

Higashibayashi, S., Mori, T., Shinko, K., Hashimoto, K., Nakata, M. Synthetic studies on thiostrepton family of peptide antibiotics synthesis of the tetrasubstituted dihydroquinoline portion of siomycin Di. Heterocycles 2002, 57, 111-122. 

The development of cell free systems has played an important role in attempts to decipher the mechanism of peptide antibiotic synthesis ". Most workers agree that this type of synthesis occurs in the complete absence of polynucleotides and that the amino acid sequence is determined by enzyme specificity and organisation in a multi-enzyme complex . The tyrocidines are produced in Bacillus brevis by an enzyme system which has been resolved into three complimentary fractions by Sephadex G-200 filtration a light and an intermediate component (molecular weight 100000 and 230000) which activate L-phenylalanine and L-proline respectively and a heavy fraction (460 000) which activates the remaining eight amino acids including L-phenylalanine. Each... 

Winnick and coworkers had described a system using cell-free extracts of Bacillus hrevis for the synthesis of gramicidin and tyrocidine. The s5mthesis appeared to be similar to that usually found for protein synthesis. It was inhibited by puromycin and chloramphenicol and was RNAase sensitive. As the galley proof for this review was being examined, a paper entitled The Biosynthesis of Gramicidin S. A Restudy was published by Winnick s laboratory (Bhagavan, Rao, Pollard, Rao, Winnick and Hall, 1966). It was reported that they were unable to repeat the previous experiments which had indicated that a ribosomal system was involved in peptide antibiotic synthesis and, consequently, a reassessment of the earlier reports was made. 

Katz, E., M. Wise, and H. Weissbach Actinomycin biosynthesis. Differential effect of chloramphenicol on protein and peptide antibiotic synthesis. J. Biol. Chem. 240, 3071 (1965). 

Antibiotics. The genes involved in the synthesis of a variety of antibiotics have been isolated (34,35). These include antibiotics such as erythromycin, streptomycin, and also peptide antibiotics such as gramicidin and tyrocidin. Characterization of these gene products facUitates the design of novel antibiotics. In addition, overexpression of some of these gene products is also expected to improve the yield of the antibiotic (34,35). 

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). 

There are some very interesting questions of stereospecificity posed by the structure and mode of operation of multienzyme complexes. Reed and Cox 35> have summarized available information on the pyruvate and a-ketoglutarate dehydrogenase complexes, and the fatty add synthetase. The mechanism of synthesis of the peptide antibiotics likewise presents interesting stereochemical problems 36>. 

Intermediates for the total synthesis of berinanamycin A, a macrocylic peptide antibiotic... 

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 ... 

Determination of the absolute configuration of 27 (a constituent of certain peptide antibiotics, the relative configuration for all racemic stereoisomers 27 - 30 was determined as summarized on p 472 and 485) by a correlation-type synthesis commencing from (S)-vinylglycine (26, R = H)203. Note that this synthesis serves only to determine the absolute configuration at C-2 of 27 (and of 29). 

It is a peptide protein synthesis inhibitor antibiotic isolated from Streptomyces capreolus. It is second line antimycobacterial drug which exhibits activity against human strains of Mycobacterium tuberculosis. 

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis. 

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

Peptides - [ANTIBIOTICS - PEPTIDES] (Vol 3) - [TRACE AND RESIDUE ANALYSIS] (Vol 24) -m beer [BEER] (Vol 4) -as endogenous opioids [OPIOIDS, ENDOGENOUS] (Vol 17) -enzymatic synthesis of [ENZYMES IN ORGANIC SYNTHESIS] (Vol 9) -radiolabeling of [RADIOPHARMACEUTICALS] (Vol20)... 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

The complex structure of peplide antibiotics adds considerably to (he problems of synthesis, but more recent efforts toward improved peptide antibiotics are encouraging. Methods of hioassay and other laboratory use of economic antibiotics are available. Table 1 is a list of important peptide antibiotics. More extensive listings of minor peptide antibiotics have been published. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

In comparison with the penicillin and cephalosporin derivatives, the peptide antibiotics are not numbered among the major antibiotics . Their action mechanisms vary, e.g. inhibition of cell-wall synthesis, increased permeability of the cell wall, or influence on nucleic acid synthesis. 

Berninamycinic acid is one of the products from acid hydrolysis of the cyclic peptide antibiotic berninamycin A, which is a potent inhibitor of bacterial protein synthesis. Berninamycinic acid has been assigned the structure (524), anhydro-3,8-dicarboxy-6-hydroxythiazolo[2,3-/][l,6]naphthyridin-4-ium hydroxide. The 6-hydroxy group arises during hydrolysis from a peptide-bonded amino group (77JA1645). 

A type I thioesterase domain is present at the NHj-terminal of the animal FAS and is responsible for catalyzing hydrolysis of the completed fatty acyl chain from the enzyme. The active site contains both conserved serine and histidine residues [87] and is thought to function via a mechanism similar to that of the serine proteases [50] however, no conserved acidic residue is present to complete the charge relay/transfer. A second variety of thioesterase (type II) is encoded as a separate protein and interacts with the multifunctional FAS to release medium chain fatty acids [88, 89]. This enzyme has a weak sequence similarity to the type I thioesterase, which includes the conserved active site serine and histidine residues. These enzymes are also homologous to proteins encoded by genes involved in the synthesis of peptide antibiotics [90,91] (see below). 

---