Polymyxins biosynthesis

A discussion of the detailed mechanism of polymyxin biosynthesis will have to await the isolation of enzyme systems that can mediate this process in vitro. However, the more general aspects of polymyxin synthesis, such as the relation of antibiotic synthesis to protein synthesis and the nature of the precursors of the peptide, can be discussed in the light of experiments carried out with growing cultures of the antibiotic producing organisms. 

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. 

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. 

In contrast to these results, the process of tyrocidine and gramicidin biosynthesis has been compared to protein synthesis, but this evidence was obtained in cell-free systems of B. brevis . Yet a difference in the mechanism of protein and antibiotic synthesis has also been reported for gramicidin polymyxin and mycobacillin and seems now to be... 

Komuta S, Kurahashi K. Biosynthesis of polymyxin E by a cell-free enzyme system. IV. Acylation of eniyme bound L-2,4-diaminobuiyric acid. J Biochem 1985 97 1409-1417. Menkhaus M. Thesis, TU Berlin, 1994. 

Konovalova LV (1970) Influence of polymyxin M on certain metabolic sites of propionic acid bacteria. PhD Thesis, Moscow State University, Moscow Konovalova LV and Vorobjeva LI (1969) Biosynthesis of B-group vitamins by propionic acid bacteria. Nauch Dokl Vys Shkoly Biol Nauki 1 91-93 Konovalova LV and Vorobjeva LI (1970) Influence of antibiotics on the growth and vitamin Bi2 biosynthesis by Propionibacterium shermanii. Nauch Dokl Vys Shkoly Biol Nauki 7 104-108... 

Paulus, H., and E. Gray The biosynthesis of polymyxin by growing cultures of Bacillus polymyxa. J. Biol. Chem. 239, 865 (1964). 

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