ISSN:
1573-501X
Keywords:
Polyketides
;
Combinatorial biosynthesis
;
Bioactive natural products
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Summary A library of over 100 polyketides, generated via combinatorial cloning of genes encoding subunits of aromatic polyketide synthases, was screened for molecules capable of inhibiting the growth of grampositive bacteria. A total of 26 polyketides, with varying levels of antibiotic activity in filter-disk assays, were purified. Most bioactive polyketides were produced as relatively minor compounds (〈 1 mg/l), although two major anthraquinones, with yields in the range of 10–100 mg/l, were also identified and structurally characterized. When tested againstBacillus subtilis 168β, they were found to cause a 50% reduction in colony-forming units at concentrations of 20 and 300 μg/ml, respectively. We speculate that many of the minor (and possibly more potent) bioactive polyketides are synthesized via nonspecific enzymatic modifications of shunt products derived from engineered polyketide synthase pathways. If so, then these ‘fortuitous’ pathways should be amenable to further rationally guided manipulation. Our results support the notion that combinatorial biosynthesis can be used to generate novel, biologically active molecules. They also point to the feasibility of designing mutagenesis selection experiments aimed at the directed evolution of organic molecules with desirable pharmaceutical properties.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01721327
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