Antibiotic biosynthesis pathways

Keywords Antibiotic biosynthesis pathways Phosphate and nitrogen control Pathway-specific regulators Streptomyces regulatory mechanisms Two component systems... 

Now that we have provided you with an overview of the history of penicillin production, we will examine some more details of the biotransformation of -lactams. We will briefly outline the normal biosynthesis pathways that lead to their production and then consider how these products may be diversified in vitro to give a wider range of valuable compounds. We begin by briefly explaining how the fi-lactam antibiotics are effective as therapeutic agents. 

Salas JA, Mendez C (2005) Biosynthesis pathways for deoxysugars in antibiotic-producing actinomycetes isolation, characterization and generation of novel glycosylated derivatives. J Mol Microbiol Biotechnol 9 77-85... 

Dr. Christophe Corre was born in Nimes, France, in 1974. He received his education in Biochemistry/Molecular Biology at the University of Nice Sophia Antipolis, France. He then carried out work on antibiotic biosynthesis in Streptomyces for which he was awarded a Ph.D. from the School of Chemistry at the University of Exeter, UK, in 2004. He is currently a postdoctoral research fellow with Professor G. L. Challis in the Department of Chemistry at the University of Warwick, UK. During his postdoctoral studies, he has worked on elucidating antibiotic biosynthetic pathways in Streptomyces codicolor and the discovery of novel bioactive natural products by genome mining. 

Polyketides are a class of antibiotics found in bacteria and fungi. Erythromycin and oxytetracycline are examples. The pathway for polyketide synthesis contains part of the fatty acid biosynthesis pathway, except that one or more of the enzymes are missing at various points in the pathway (Figure 18.35). This leads to a diverse set of products containing internal hydroxyls and ketone groups. 

Antibiotic biosynthetic enzymes are generally believed to possess low substrate specificity. This can be rationahzed fi-om an evolutionary point of view reduced substrate specificity increases the probability of a chain of enzymes to yield a product, even when the enzymes form new combinations (Fig. 1). When the intermediates are structurally distinct from the intermediates of primary metabolism, there is little need for stringent selectivity (and thus httle evolutionary pressure to increase it) as no competing intermediates are present. Since the evolutionary advantage in antibiotic biosynthesis originates from the diversity of the compounds produced and is rather indifferent to the quantity of production, many pathways have converged such that a long chain of enzymes with broad substrate specificity yields a specific product. 

Further examples of the family of fattiviracin antiviral antibiotics with different lengths of fatty acid chains (see Vol. 32, p. 244) include compound 88. Compound 89, with R = 2,3-di-0-methyl-a-L-fucosyl-(l- 3)-2,4-dimethyl-p-D-xylose, is a powerful toxic metabolite of the red alga Polycavernosa tsudai and its total synthesis has been reported. The biosynthesis pathways to vicenistatin 1, 90 (R = 2,4,6-trideoxy-4-methylamino-p-D-riho-hexose) and vicenistatin 2, 90... 

The two antibiotics with which PPIs synergize are amoxicillin and clarithromycin. The former antibiotic inhibits cell wall biosynthesis by inhibiting peptidyl transferase and by binding to other proteins in the cell wall biosynthesis pathways. Cell division is therefore required for the bactericidal action of this class of antibiotic. Clarithromycin binds to the 23S RNA and thereby inhibits protein synthesis. Hence, protein synthesis is required for the action of this antibiotic. Metronidazole is reduced to the hydroxylamine derivative, which then binds to DMA, hence not requiring cell division or protein synthesis for its efficacy. PPIs do not synergize with this antibiotic. Resistance to metronidazole develops by decrease of the level of reducing enzyme and, therefore, may be relative or absolute. Resistance to clarithromycin occurs by a base mutation at the binding site on the RNA and is usually absolute. 

With ethyl-AMP and AMPI specific inhibitors of the two independent routes of acetyl-CoA formation in plastids are available. Several specific xenobiotics block efficiently de novo fatty acid biosynthesis at different steps and enzyme levels (Figure 3). Graminicides such as diclofop, sethoxydim or cycloxydim are specific inhibitors of acetyl-CoA carboxylase (ACCase) of grasses [10], the antibiotics cerulenin and thiolactomycin are inhibitors which affect certain of the li-ketoacyl-ACP synthases (KAS I, II and III). With these xenobiotics one can control the metabolite flow through the fatty acid biosynthesis pathway and obtain a better understanding of the regulation of the plants de novo fatty acid biosynthesis and the enzymes involved. 

Bister, B., Bischoff, D., Strdbele, M., Riedlinger, J., Reicke, A., Wolter, F., Bull, A.T., Ziihner, H., Fiedler, H.P., and Siissmuth, R.D. (2004) Abyssomidn C - A polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor of the p-aminobenzoic acid/tetrahydrofolate biosynthesis pathway. Angew. Chem. Int. Ed., 43, 2574-2576. 

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