The primary focus in the continuation of our studies on the biosynthesis of antibiotics and other microbial metabolites will be on three Actinomycete antibiotics which contain mC7N units of different biosynthetic origin. These are rifamycin, an antitubercular drug whose semisynthetic derivatives, like rifampicin, are widely used clinically, asukamycin, a member of a family of compounds which have shown, inter alia, inhibition of protein prenylation and of interleukin-1beta converting enzyme, and validamycin, a commercial agent against phytopathogenic fungi but also the precursor for the synthesis of the clinical antidiabetic drug, voglibose. In all three cases the object is to define the biosynthetic pathway and its genetic control, and to unravel key biochemical reaction mechanisms involved in these biosyntheses by a combination of molecular biological and biochemical approaches, and to lay the foundation for the generation of modified bioactive structures through genetic engineering. A secondary focus is on the elucidation, at the genetic, enzymatic and mechanistic level, of the mode of formation of the 2,6-dideoxyhexose moieties of the unusual macrolide antibiotic, chlorothricin, and of the formation and mode of attachment of the 2,6-dideoxy- and 2,3,6- trideoxyhexose moieties of the benzoisochromane quinone antibiotic, granaticin. These studies will help provide the knowledge base and the tools to modify the structures of various bioactive natural products by the attachment of different sugar moieties. Thirdly we will complete ongoing studies on the biosynthesis of phenazine antibiotics, the saphenamycins and esmeraldins, with the aim of identifying unequivocally the structure of the monomeric shikimate pathway derivative which undergoes dimerization to the general precursor, phenazine-1,6-dicarboxylic acid, and on the thiopeptide antibiotics, nosiheptide and thiostrepton, aimed at cloning the correct peptide synthases encoding their formation.
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