Polymyxins structure-activity

The possible effects of such modifications are of several kinds, some not directly concerned with therapeutic efficacy. In its new form the antibiotic may be more stable, more soluble, more palatable (chloramphenicol palmitate), better absorbed (erythromycin estolate), or less irritant to the tissues (polymyxin methane sulfonate). Some of the most far-reaching effects produced by a minor structural change are seen in demethylchlortetracycline, which, as compared with tetracycline, is more stable, antibacterially more active, and much more slowly excreted. 

It is still premature to give a clear correlation between structure and activity in the polymyxin group, because most published data on antimicrobial activity have been obtained either with impure material or with mixtures of the different individuals. Also the definition of potency differs for those antibiotics which were considered to be different up to now. But the synthesis " of the four compounds originally proposed by Hausmann with a D-a,y-diaminobutyric acid adjacent to the fatty acid and the synthesis of polymyxin Bj and colistin A have given some clues in these respects Table 1.12). 

Polymyxins, fatty acid-containing, branched cyclic peptides produced by Bacillus polymyxa possessing antibiotic activity against Gram-negative bacteria. The structure of polymyxin Bi is shown as a member of this peptide group. The basic sequence of polymyxins consists of... 

The lipolytic activity of propionibacteria was shown to be higher than that of lactic acid bacteria (Depuis et al., 1993). Propionibacterial lipids apparently are not only structural components of the cell, but may also have a protective role against the action of some antibiotics. In the presence of polymyxin M (Konovalova, 1970) the production of lipids and phospholipids was increased (Fig. 4.15). 

The polymyxins are a group of closely related lipopeptide antibiotics produced by B. polymyxa and related bacilli. As seen in O Fig. 10.5, polymyxin B is a decapeptide in which amino acids 3 through 10 form a cyclic octapeptide. A branched-chain fatty acid is connected to the terminal 2,4-diaminobutyric acid (DAB). The structures of polymyxins differ in substituents at residues 3 (DAB or D-Ser), 6 (o-Leu or L-Ileu), or 7 (d- or l-DAB) (Suzuki et al. 1965). The cationic 7y-amino groups of the DAB residues, together with the hydrophobic side chain of the fatty acid, give these antibiotics the surface-active properties of a cationic detergent. Pseudomonas strains produce viscosin, a peptidolipid biosurfactant which lowers surface tension of water to 27 mN/m (Neu et al. 1992). 

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