Some Acetate Derived Antibiotics

Abstract

The present body of knowledge concerning the biosynthesis of antibiotic substances and of related but less pharmacodynamically active secondary and tertiary fungal metabolites is based upon the monumental researches of Raistrick (1949) and his coworkers, who over a quarter-century isolated and characterized many of the substances under consideration in this chapter. Structural relationships among certain of these mold products led Birch and Donovan (1953) to postulate that they are formed from condensation of acetate units (or of other acyl-CoA derivatives) via the intermediation of poly-β-ketides. At about the same time, Aghoramurthy and Seshadri (1954), based upon their structural survey of mold metabolites, proposed a central role for orsellinic acid. These important hypotheses led to a period of radioactive precursor incorporation studies. During this time the validity of the acetate condensation path was fully established, and the analogy between fungal aromatic synthesis and mammalian fatty acid biosynthesis (Rittenberg and Bloch, 1945) was strengthened. A major breakthrough in the understanding of the mechanism of fatty acid formation was the finding (Brady, 1958; Wakil, 1958), that the driving force for C2-unit condensation involves malonyl-CoA as a reactant; and tracer experiments shortly thereafter (Mosbach, 1961; Bentley and Keil, 1961; Bu’lock and Smalley, 1961; Birch et al., 1961) demonstrated that this acetate-polymalonate pathway was also operative in secondary metabolite formation by the higher fungi. As this generalized pattern for the poly-acetate route to aromatic structures (Lynen and Tada, 1961) became more fully delineated, it was clear that further advances in this area would probably result from increased emphasis on studies with cell-free enzyme systems (Bassett and Tanenbaum, 1960) and from the use of biochemical mutants (cf. Bassett and Tanenbaum, 1958). Rapid progress has, however, been hampered by lack of generally applicable, reproducible methods for obtaining cell-free extracts from the fungal mycelium, coupled to the discouraging fact that detectable intermediates in fatty acid synthesis (ALBERTS et al., 1963; Brodie et al., 1963) or in fatty acid oxidation (Drysdale and Lardy, 1953) have not been found. The inherent instability of higher poly-β-ketides in the free linear state, (Collie, 1907) also makes the isolation of presumptive fungal intermediates unlikely, although the stabilized pyrone form of a lower, methylated oligoketide (Brenneisen et al., 1964) has been obtained from Penicillium stipitatum. In the near future, it is conceivable that the combined application of suitably labelled novel organic intermediates, such as the stable polypyrone acetate-malonate progenitors of Money et al. (1965), to cell-free multienzyme synthetic systems (Gatenbeck and Hermodsson, 1965), may lead not only to striking advances in our understanding of antibiotic biosyntheses, but may also provide a facile route for the production of trial quantities of antibiotic analogs.

“.... there are signs of order and of a general underlying design in the biochemistry of fungi. I share Haldane’s view that by the careful investigation .... of mutants .... much may be learned about the intermediate metabolism of these organisms”.

H. Raistrick (1949)

Symbols used. labelled carbons derived from acetate-1-¹⁴C and acetate-2-¹⁴C respectively; from labelled formate or methyl-¹⁴C-methionine or their biological equivalents; radioactive position in a synthetic precursor; labelled positions derived from mevalonic-2- or -4-¹⁴C, respectively. Other specialized labels as depicted in the figures.