ABSTRACT
Supplementing an AHBA(-) mutant strain of Amycolatopsis mediterranei, the rifamycin producer, with a series of benzoic acid derivatives yielded new tetraketides containing different phenyl groups. These mutasynthetic studies revealed unique reductive properties of A. mediterranei towards nitro- and azidoarenes, leading to the corresponding anilines. In selected cases, the yields of mutaproducts (fermentation products isolated after feeding bacteria with chemically prepared analogs of natural building blocks) obtained are in a range (up to 118 mg L(-1)) that renders them useful as chiral building blocks for further synthetic endeavors. The configuration of the stereogenic centers at C6 and C7 was determined to be 6R,7S for one representative tetraketide. Importantly, processing beyond the tetraketide stage is not always blocked when the formation of the bicyclic naphthalene precursor cannot occur. This was proven by formation of a bromo undecaketide, an observation that has implications regarding the evolutionary development of rifamycin biosynthesis.
Subject(s)
Actinomycetales/chemistry , Anti-Bacterial Agents/biosynthesis , Azides/chemistry , Biological Products/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Hydro-Lyases/chemical synthesis , Multienzyme Complexes/biosynthesis , Multienzyme Complexes/chemistry , Naphthalenes/chemical synthesis , Polyketide Synthases/chemistry , Rifamycins/chemistry , Rifamycins/chemical synthesis , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Bridged Bicyclo Compounds/chemistry , Hydro-Lyases/chemistry , Hydro-Lyases/metabolism , Magnetic Resonance Spectroscopy , Molecular Structure , Naphthalenes/chemistry , Polyketide Synthases/metabolism , Rifamycins/biosynthesisABSTRACT
Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.
