Bacitracins structure

Systemic therapy with a variety of (3-lactams, macro-lides and lincosamides (clindamycin) has been the cornerstone of skin infection therapy for many years [17]. However, topical antibiotics can play an important role in both treatment and prevention of many primary cutaneous bacterial infections commonly seen in the dermatological practice [18], Indeed, while systemic antimicrobials are needed in the complicated infections of skin and skin structure, the milder forms can be successfully treated with topical therapy alone [18], The topical agents used most often in the treatment of superficial cutaneous bacterial infections are tetracyclines, mupirocin, bacitracin, polymyxin B, and neomycin. 

Bacitracin biosynthesis requires a non-ribosomal peptide synthetase with three major protein components, BacABC. This synthetase has a modular structure. There are associated regulatory and transport systems. Biosynthesis of bacitracin has been engineered in the surrogate host, B. subtilis, by genetic techniques. A strain, B. subtilis KE 350, expresses the entire 49-kb bacitracin... 

The answer is c. (Hardman, pp 1143-1144.) Bacitracin, cycloserine, cephalothin, and vancomycin inhibit cell-wall synthesis and produce bacteria that are susceptible to environmental conditions. Polymyxins disrupt the structural integrity of the cytoplasmic membranes by acting as cationic detergents. On contact with the drug, the permeability of the membrane changes. Polymyxin is often applied in a mixture with bacitracin and/or neomycin for synergistic effects. 

An interesting example of MIP-LC analytics was presented in a paper, which focused on the separation of antibiotics of similar structures. Columns are (commercially) available to separate penicillins ( 3-lactams) from other antibiotics. However, if the quantification of each of the 3-lactam compounds is required, a more selective stationary phase has to be found. Molecular imprinting allows the fabrication of phases specifically for each 3-lactam. If for instance the concentration of the P-lactam oxacillin in a food sample has to be selectively determined, a polymer imprinted with oxacillin is the right choice. Compared to a standard stationary phase, which only allowed the separation of the entire group of (5-lactams from other non-(3-lactam analytes (e. g., bacitracin), the MIP enables the separation of the imprinted species from the pair of non-imprinted 3-lactams penicillin V and penicillin G see Fig. 6 [29,30]. 

Fig. 6. A Chromatogram of a mixture containing the print molecule (oxacillin), two other p-lactam-antibiotics (penicillin G and penicillin V) and a non- 3-lactam-antibiotic (bacitracin) on an oxacillin imprinted MIP containing 4-vinylpyridine residues, cross-linked with TRIM. The analysis was performed in organic mobile phase (ACN/AcOH,99 l).B Same conditions but using the respective non-imprinted control polymer. C Structures of penicillin V, penicillin G, and oxacillin. Reprinted with permission from Skudar K, Briiggemann O, Wittelsberger A, Ramstrom O (1999) Anal Commun 36 327. Copyright 1999 The Royal Society of Chemistry...

Our approach has been essentially empirical in nature with less emphasis on the theoretical. We have isolated single substances, proved their purity, and determined their covalent structure by classical methods of organic chemistry we have then used these substances of molecular weight ranging from 1,000 to 14,000 as model solutes for the study of conformation and intermolecular interaction. Solutes of special interest have been gramicidin SA (2), bacitracin A (3), polymyxin B, and the tyrocidines A, B, and C (4). All are cyclic antibiotic polypeptides. The first three behave in aqueous solution as reasonably ideal solutes and do not associate, but the tyrocidines associate strongly and are interesting models for the study of association phenomena. Other model solutes of... 

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

X-Ray crystallography has been employed to demonstrate that, in the solid state, histamine is 5-(2-aminoethyl)imidazole, a result which contrasts with the structure determined for its cation. However, from determinations of pXa values of histamine and its two possible methyl derivatives, a Kt value of 4 (4- 5-substituted isomer) has been found. In fact, in aqueous solution histamine exists largely as the protonated form (31) which reverts to (32) on neutralization. Electron-withdrawing groups in the imidazole ring of histamine cause the 4-isomer to predominate, but methyl groups have little effect (80AHC(27)24l). The 4-substituted zwitterionic form for histidine is preferred in basic medium this form is maintained in a number of histidine derivatives (e.g. the polypeptide bacitracin). 

Figure 2 A selection of nonribosomal peptides. Chemical and structural features that contribute to the vast diversity of this class of metabolites are highlighted Heterocycle (bacitracin), lactone (surfactin, daptomycin), ornithine and lactam (Tyrocidine), sugar, chlorinated aromats, C-C crosslink (Vancomycin), N-formyl groups (Coelichelin and linear gramicidin), fatty acid (daptomycin), dihydroxybenzoate and trimeric organization (bacillibactin), dimeric organization (gramicidin S), and ethanolamine (linear gramicidin).

Together with the derivatives of pyridine, the thiazoles soon constituted an important part of heterocyclic chemistry, as much from the point of view of the initial research as from the practical aspect. Their biological and pharmaceutical interest is in fact important as they appear in the composition of certain vitamins such as vitamin Bj (thiamine) and in the penicillins. Reduced thiazoles serve in the study of polypeptides and proteins and occur as structural units in compounds of biological significance, for example, firefly luciferins and in antibiotics bacitracin A and... 

Classical enzyme inhibitors such as bacitracin, bes-tatin, and amastatin have been found to be effective for improving the nasal absorption of various peptide drugs such as LHRH and calcitonin. These inhibitors having peptide like structures appear to exert their inhibitory effects by a competitive mechanism. In addition, camostat mesilate and nafamostat mesilate, which are clinically used as primary ingredients for pancreatic diseases, have been found to improve the nasal absorption of vasopressin, desmopressin, and calcitonin by inhibiting aminopeptidase and trypsin activity. 

Bacitracin is a basic cyclic peptide antibiotic consisting of more than 20 components, but, except for the major components BC-A and BC-F, the chemical structures of other components are still unknown. 

The prineipal work on the chemistry of the bacitracins been directed toward bacitracin A. the component in thicb most of the antibacterial activity of crude bacitraein [Pg.357]

After the Second World War, the effort continued to find other novel antibiotic structures. This led to the discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (Fig. 10.72) (1947), the tetracycline antibiotics (e.g. chlortetracycline (Fig. 10.71) (1948)), the macrolide antibiotics (e.g. erythromycin (Fig. 10.73) (1952)), the cyclic peptide antibiotics (e.g. cycloserine (1955)), and in 1955 the first example of a second major group of (3-lactam antibiotics, cephalosporin C (Fig. 10.41). 

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