Antibiotic peptides

PEPTIDES, PROTEINS, AND OTHER AMINO ACID DERIVATIVES 

Bleomycin is a mixture of glycopeptide antibiotics isolated from cultures of Streptomyces verticillus, used for its anticancer activity. The major component (55-70%) of the mixture 

Peptide antibiotics are compounds containing amino acids that are covalently linked to other chemical entities and consist of more than one component. In contrast to naturally occurring proteins that are built up from L-amino acids only, peptide antibiotics usually contain o-amino acids. Avoparcin, bacitracin, efroto-mycin, enramycin, thiopeptin, and virginiamycin constitute the main members within this group of drugs (Fig. 6.2). They are usually added to animal feeds at low concentrations, and produce residues in tissues at very low or undetectable levels. Unfortunately, the metabolic pathways of most peptide antibiotics have not been still elucidated. Within the European Union, these antibiotics are regulated under a separate legislation (Directive 70/524/EEC). 

In ruminants, avoparcin has a dual action. It acts in the rumen by enhancing fermentation, and in the intestine by improving the absorption of nutrients. Following feeding to animals, avoparcin is virtually unabsorbed from the gastrointestinal tract and is rapidly eliminated in the form of the parent compound. As a result, no withdrawal period is required. 

Bacitracin is a linear-ring peptide antibiotic produced by Bacillus subtilis and Bacillus licheniformis. Commercial formulations of bacitracin comprise a mixture of many closely related compounds classified into bacitracin A, B, C, D, E, F, and G (5). The main components are bacitracin A, B, and B2, constituting 57%, 22%, and 13%, respectively, of the mixture, whereas bacitracin F constitutes less than 2%. Bacitracin F is actually a degradation product of bacitracin A that 

After oral application, bacitracin is hardly absorbed by the gastrointestinal tract and, therefore, its distribution in tissues is considered negligible (6). Approximately 95% of an orally administered dose is excreted via feces, and only 3% or less via urine. Bacitracin is primarily metabolized to desamidobacitracin and further to smaller peptides and amino acids. Main metabolites identified in feces are bacitracin A, Bi, B2, F, desamidobacitracin, and catabolic peptides. In urine and bile, only hydrolytic cleavage products such as small peptides are present. 

Intramammary use of bacitracin resulted in residues in milk, but not in plasma, udder, or any other tissue. Residue depletion studies in cows given intramammary bacitracin treatment showed that muscle, liver, kidney, fat, udder, and milk from untreated quarters did not contain detectable residues ( 0.003-0.005 lU/ml) after the end of treatment. In milk from treated quarters, however, residues of bacitracin could be detected during treatment, declining to around 0.04 lU/ml at the sixth milking after treatment. 

Peptide antibiotics include a wide range of compounds such as cycloserine (an amino acid), bacitracin (a cyclic peptide), thiostrepton (a Unear peptide), neocarzinostatin (a polypeptide) and bleomycin (a glycoprotein). These compounds possess either antibacterial and/or antitumor activity and should be regarded as conventional peptides for the purposes of HPLC. For a detailed overview of the HPLC retention times of the more common peptide antibiotics in various buffer systems the reader is referred to a recent review (Aszalos and Aquilar, 1984). The recommended stationary phase is a Vydac RP-18 column because it produced the least amount of peak taiUng. Mobile 

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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). 

Nikkomycins. The nikkomycins (141—159), isolated from S. tendae are nucleoside-peptide antibiotics (1,4,244,245) as shown in Table 8. Nikkomycins X and Z are stmcturaHy identical to neopolyoxins A and C, respectively. Compound (141) is a competitive inhibitor of chitin synthetase. Two new nikkomycins, nikkomycin pseudo-Z and pseudo-J (158, 159), contain a C-glycosidic bond between C-5 of uracil and C-1 of... 

Several economically useful peptide antibiotics are produced by members of the bacterial genus bacillus. 

Most peptide antibiotics have been isolated from Jictinomycetes and especially from Streptomjces. Many P-lactams, however, and a few other useful peptide antibiotics have come from fungi. These streptomycete and fungal peptide antibiotics include many stmctural types having varied therapeutic indications and/or scientific appHcations. 

Bleomycin and cyclosporine are the two economically most important streptomycete peptide antibiotics used as antitumor agents and immunomodulators, although dactinomycin is important medically for several tumors (see Chemotherapeutics, anticancer Immunotherapeutic agents). 

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). 

FIGURE 10.35 The amino acid sequences of several amphipathic peptide antibiotics, a-Helices formed from these peptides cluster polar residues on one face of the helix, with nonpolar residues at other positions. 

Protected 3-methyl-D-cystein (257 Scheme 3.94), a structural unit of the peptide antibiotics nisin and subtilin, has been synthesized through the ring-opening of the aziridinecarbamide 254 with thiobenzoic acid (255) [143, 144]. The reaction took place overnight at room temperature and in methylene chloride to give 256 in greater than 95% yield. 

Many peptide antibiotics have novel structural motifs, such as cyclic structures and are often further modified, (such as in jS-lactamic antibiotics) and conjugated with sugars, lipids, and other molecules. 

FIG. 9 A scheme representing lateral phase separation for anionic lipids from zwitterionic lipids in a mixed lipid bilayer induced by the peptide antibiotic, polymyxin-B. (Reprinted by permission from Ref. 41, copyright 1998, Elsevier Science.)... 

Fischbach, M.A. and Walsh, C.T. (2006) Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics logic, machinery, and mechanisms. Chemical Reviews, 106, 3468—3496. 

Walsh, C.T. (2004) Polyketide and nonribosomal peptide antibiotics modularity and versatility. Science, 303, 1805. 

Mootz, H.D. and Marahiel, M.A. (1997) Biosynthetic systems for nonribosomal peptide antibiotic assembly. Current Opinion in Chemical Biology, 1 (4), 543—551. 

Brandi, L., Fabbretti, A., La Teana, A., Abbondi, M., Losi, D., Donadio, S., and Gualerzi, C. O. (2006b). Specific, efficient, and selective inhibition of prokaryotic translation initiation by a novel peptide antibiotic. Proc. Nat. Acad. Sci. USA 103, 39-44. 

John Sheehan s major research achievements are described in some 150 synthetic papers which cover not only penicillin, but peptides, antibiotics, alkaloids and steroids. For these scientific contributions John received several high honors including the American Chemical Society award in Pure Chemistry (1951), the American Chemical Society award for Creative Work in Synthetic Organic Chemistry... 

McCafferty DG, Cudic P, Frankel BA, Barkal-lah S, Kruger RG, Li W Chemistry and biology of the ramoplanin family of peptide antibiotics. Biopolymers 2002,66 261 -284. 

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. 

Pentynoic acid, 5 34t People. See also Personnel investment in, 21 624 organizational ties to, 21 627-628 People s Republic of China. See also China demand for oil in, 23 530 oil recovery program in, 23 534 Pepper, pipeline levels in, 23 159 Peptide antibiotics, 18 252-253. See also Antimicrobial peptides Peptide backbone hydrogen bonds, in proteins, 20 826 Peptide mapping, 3 840-841 Peptide nucleic acids, 17 631-634... 

From Streptomyces cirratus 248-Sq2, cirratiomycin A (133, R = iBu) has been obtained, and has been found to be active in vitro against a narrow range of Lactobacillus and some strains of Streptococcus [367]. In addition, the peptide antibiotic (132, R = Me) is also produced by this Streptomycete [367]. 

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