Compositions and methods for activation and overexpression of secondary metabolites in microorganisms

摘要

Methods and compositions herein provide non-naturally occurring γ-butyrolactones (GBLs) in racemic mixtures that increase efficiency and effectiveness of screening for production of antibiotics, and enhance yields and express silent pathways. Non-naturally occurring GBLs were synthesized and found to stimulate antibiotic production in several different streptomycete strains. Antibiotic production by Streptomyces coelicolor was induced by a racemic mixture of non-cognate stereoisomers of VB-D, seven of which are non-naturally occurring. Further, novel A-factor-type GBL analogs stimulated antibiotic production in S. coelicolor. Synthesis in response to the treatment with the non-cognates GBL was observed for known compounds including undecylprodigiosin, desferrioxamine and streptorubin B, as was synthesis of a compound of unknown structure. A group of 37 additional microbial strains was screened by principal component analysis to determine optimal concentrations of each of a panel of four non-cognate synthetic GBLs for addition to cultures with optimal stimulation of secondary metabolites, and large scale fermentations were analyzed and product enhancement by the GBLs was observed.