Polymyxins 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. 

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. 

Disruption of bacterial membrane structure Polymyxins Colistin Altered target Efflux... 

Compounds that disrupt cell membrane integrity either through structural or functional disorganization lead to loss of viability. Polymyxins and daptomycin (Fig. 5) are examples of cell membrane inhibitors. 

Threonine and a,7-diaminobutyric acid are present within the structure of these antibiotics. The distinguishing feature of the polymyxine group is in that they contain 4-5 free / amine groups of a,7-diaminobutyric acid, which gives them the property of a cationic detergent able to form complexes with phospholipids of cellular membranes. All polymyxines are similar in term of antibiotic action. 

Polymyxins (bactericidal disrupt bacterial membrane structural integrity)... 

Fig. 3.9 Chemical structures of colistin, polymyxin, rifaximin, rifamycin SV, novobiocin, and tiamulin.

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... 

Colistin (COL) is a multicomponent antibiotic (polymyxins E) that is produced by strains of inverse Bacillus polymyxa. It consists of a mixture of several closely related decapeptides with a general structure composed of a cyclic heptapeptide moiety and a side chain acetylated at the N-terminus by a fatty acid. Up to 13 different components have been identified. The two main components of colistin are polymyxins El and E2 they include the same amino acids but a different fatty acid (216). A selective and sensitive HPLC method was developed for the determination of COL residues in milk and four bovine tissues (muscle, liver, kidney, and fat). The sample pretreatment consists of protein precipitation with trichloracetic acid (TCA), solid-phase purification on Cl 8 SPE cartridges, and precolumn derivatization of colistin with o-phthalaldehyde and 2-mercaptoethanol in borate buffer (pH 10.5). The last step was performed automatically, and the resulting reaction mixture was injected into a switching HPLC system including a precolumn and the reversed-phase analytical column. Fluorescence detection was used. The structural study of El and E2 derivatives was carried out by HPLC coupled with an electrospray MS. Recoveries from the preseparation procedure were higher than 60%. 

Trent, M.S., Ribeiro, A.A., Doerrler, W.T., Lin, S., Cotter, R.J., Raetz, C.R.H. Accumulation of a polyisoprene-linked amino sugar in polymyxin resistant mutants in Salmonella typhimurium and Escherichia coli structural characterization and possible transfer to lipid A in the periplasm. J Biol Chem 276 (2001a) 43132-43144. 

Ortega, X., Silipo, A., Saldfas, M.S., Bates, C.C., Molinaro, A., Valvano, M.A. Biosynthesis and structure of the Burkholderia cenocepacia K56-2 lipopolysaccharide core oligosaccharide truncation of the core oligosaccharide leads to increased binding and sensitivity to polymyxin B. J Biol Chem 284(32) (2009) 21738-21751. 

Moskowitz, S.M., Bums, J.L., Nguyen, C.D., Hftiby, N., Ernst, R.K., Miller, S.I. Polymyxin resistance and lipid A structure of Pseudomonas aeruginosa isolated from colistin-treated and colistin-naive cystic fibrosis patients. Pediatr Pulmonol Suppl 20 (2000) 272. 

Fig. 12.14 Left Structures of mono-substituted alkylpolyamines (AKla-5a), two bri-substituted analogues (AK6b, 7b) were also synthesized and examined for SAR confirmation. Right Inhibition of LPS (100 ng/mL)-induced NF-kB induction in HEK-293 cells stably transfected with Tlr4, MD-2, CD 14, and an NF-icB-secreted alkaline phosphatase reporter gene construct. Polymyxin B was used as the positive control...

Ingram, B., Sohlenkamp, C., Geiger, O., Raetz, C.R. Altered lipid A structures and polymyxin hypersensitivity of Rhizobium etli mutants lacking the LpxE and LpxF phosphatases. Biochim Biophys Acta. Biochem. Biophys. Acta 1801 (2010) 593-604. 

Polymyxin B sulfate is a nearly odorle.ss. white to buff powder. It is freely soluble in water and slightly soluble in alcohol. Its aqueous solutions are slightly acidic or nearly neutral (pH 5 to 7.5) and. when refrigerated,. stable for at least 6 months. Alkaline. solutions are unstable. Polymyxin B was shown to be a mixture by Haasmann and Craig. who used countercurrent distribution techniques to obtain two fractions that differ in. structure only by one fatty acid component. Polymyxin B, contains ( +)-6-methyloctan-l-... 

Chemically, colistin is a polypeptide, reported by Suzuki (1 al.. whose major component is colistin A. They pro-pt sed the structure shown below for colistin A. which differs hnm polymyxin B only by the substitution of n-leucine for isphcnylalanine as one of the amino acid fragments in the. jclic portion of the structure. Wilkinson and Lowe have c lTToboraied the structure and have shown that colistin A is iihiiiul with polymyxin Ej. 

Polymyxin E (colistin) is used in the treatment of serious Gram-negative bacterial infections, particularly those caused by Pseudomonas aeruginosa. It binds tightly to the lipid A component of LPS in the outer membrane of Gram-negative bacteria. The outer leaflet of the membrane structure is distorted, segments of which are released and the permeability barrier is destroyed. The polymyxin mole-... 

A strain of B. -polymyxa produces an antibiotic which has been named polymyxin. A group of workers at the American Cyanamid Co. have attempted to isolate it. They have gone far toward structure... 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

---