Peptide-type antibiotics

Brevin, Brevolin and Edein, three peptide antibiotics with structures yet unknown, are not in clinical use Table 1.4). Tyrothricin consists of a whole group of chemically and biologically closely related individuals, a feature known for the polymyxins, the bacitracins and other peptide-type antibiotics. The tyrothricin group is interesting not only because of its clinical application, but also from a historical viewpoint. Tyrothricin was the second antibiotic found, 10 years after the discovery of penicillin, in a direct search for antibiotic substances. As the first antibiotic of strictly peptide nature, it... 

A detailed method for the investigation of peptide-type antibiotics, including bleomycin and gramicidin, by means of TLC on RP-C g plates (Analtech) was published (40). Different aqueous modifiers and buffers were used 80% methanol, 60% acetonitrile, 40% tetrahydrofuran, heptane sulfonic acid sodium salt, and NaH2P04. The effects of these components can be seen in Table 14. 

Most biologically active natural peptides are linear, but bacitracin is a leading member of the so-called cyclic peptide type of antibiotics. The commercial material, extracted from Bacillus subtilis, is a mixture of several compounds in which bacitracin A predominates. It exerts its action by inhibiting peptidoglycan synthesis and membrane function. Bacitracin has been a useful antibiotic since the 1960s, but its systemic use results in a number of toxic side effects, including nephrotoxicity. One cannot be sure which components of the mixture are responsible for the toxicity, and separation of natural constituents is complex and difficult. For this reason, an efficient synthesis of bacitracin A would be useful. 

NMR of Glycopeptide (Vancomycin-Type) Antibiotics Structure and Interaction with Cell Wall Analogue Peptides... 

Macrocyclic antibiotics such as vancomycin or teicoplanin are large molecules with several peptide-type ring structures (besides numerous phenyl rings) moreover they are glycosylated. They can be used in the normal-phase and reversed-phase mode as well. 

Recktenwald J, Shawky R, Puk O, Pfennig F, Keller U, Wohlleben W, Pelzer S (2002) Nonribosomal biosynthesis of vancomycin-type antibiotics a hep-tapeptide backbone and eight peptide synthetase modules. Microbiology 148 1105-1118... 

High performance liquid chromatography is well established as a tool for the separation of mixtures of labile biological substances, but its combination with mass spectrometry (LC/MS) remains fraught with difficulties as a valid analytical procedure. Several new types of direct liquid introduction interfaces (as opposed to transport interfaces) have been developed recently and appear to offer promise for the future. The thermospray interface 44) has been used successfully for amino acids, small peptides, nucleosides, antibiotics and glucuronides. The spectra are the relatively simple ones commonly obtained from soft ionization methods and resemble those obtained by FABMS. A gas nebulizer interface has enabled representative spectra (resembling those generated from DCI) to be... 

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. 

Another type of intestinal peptide transporter, hPTl, which is significantly different in sequence from PEPT1, was identified using a functionally inhibitory monoclonal antibody [99]. This transporter is widely expressed in the human GI tract and facilitates the oral absorption of pdactam antibiotics and ACE inhibitors from the intestine [18, 99]. Interestingly, we recently reported that hPTl gene expression is approximately 4-fold higher than PEPT1 in the human duodenum [4] (Fig. 11.1). 

This enzyme [EC 3.4.16.4], also known as serine-type D-alanyl-D-alanine carboxypeptidase, catalyzes the hydrolysis of D-alanyl-D-alanine to yield two D-alanine. This enzyme comprises a group of membrane-bound, bacterial enzymes of the peptidase family Sll. They are distinct from the zinc D-alanyl-D-alanine carboxypeptidase [EC 3.4.17.14]. The enzyme also hydrolyzes the D-alanyl-D-alanine peptide bond in the polypeptide of the cell wall. In addition, the enzyme will also catalyze the transpeptidation of peptidyl-alanyl moieties that are A-acetyl-substituents of D-alanine. The protein is inhibited by j8-lactam antibiotics, which acylate the active-site seryl residue. 

A quite new type of antibiotic and one of the few naturally-occurring boron compounds is boromycin (86). Hydrolytic cleavage of D-valine with the M(7) hydroxides gave caesium and rubidium salts of this antibiotic, and crystal structure analysis established the formula as (XIIT). The rubidium ion is irregularly coordinated by eight oxygen atoms. Experiments with models showed that the cation site would be the natural place for the—NH3+ end of the D-valine residue, and the whole structure raises the possibility that transport of larger alkali metals is related to the N-ends of peptides and proteins. 

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). 

The study of enzymatic reactions in systems with substrates present at very high mass/volume ratios, often leading to suspensions rather than solutions, has also been pursued. The majority of the published work on this type of reaction was related to the synthesis of protected peptides [3-15], but the synthesis of beta-lactam antibiotics [16-19], glycosides [20, 21], glycamides [22], and esters [23-27] starting from suspended substrates has also been reported. 

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). 

---