Structure elucidation of new ascomycins produced by genetic engineering

Abstract

Three new ascomycins produced by genetic engineering of Streptomyces hygroscopicus ATCC 14891 have been purified and characterized. Replacement of the 13-methoxyl group of ascomycin was accomplished by substitution of the corresponding acyltransferase domain of the polyketide synthase with a domain specific for either malonyl-CoA or methylmalonyl-CoA. The strain containing the methylmalonyl-specific acyltransferase domain produced a compound with properties consistent with those expected for 13-demethoxy-13-methylascomycin. NMR analysis revealed this material to be predominantly the cis amide rotamer, similar to ascomycin. The strain containing the malonyl-specific acyltransferase domain produced a mixture of two compounds, 13-demethoxyascomycin and the 9,14-hemiacetal isomer of 13-demethoxyascomycin, in nearly equal amounts. NMR analysis revealed both compounds to be predominantly the trans amide rotamers. © Japan Antibiotics Research Association.