Chemistry

A method of using bacterial enzymes to add prenyl groups to aryl-containing scaffolds could enable the discovery of novel bioactive molecules. The single-step chemical reaction involved utilizing C-prenyltransferases derived from a Streptomyces species and two species of Aspergillus fumigatus as catalysts to transfer a prenyl functional group from a donor molecule, such as dimethylallyl pyrophosphate, to the aryl ring of a drug-like molecule. On a range of indoles and other aryl-containing small molecules, the method utilizing the Streptomyces C-prenyltransferase (priB) produced prenylated analogs in yields of up to 99%. On the antibiotic Cubicin daptomycin, the method utilizing each of the three C-prenyltransferases produced prenylated Cubicin analogs that inhibited the growth of Staphylococcus aureus, Micrococcus luteus and Bacillus subtilis with lower minimum inhibitory concentration (MIC) values (0.1-0.3 µM, 0.03-0.09 µM and 0.2-0.5 µM, respectively) than Cubicin (0.6, 0.15 and 2 µM, respectively). Next steps include expanding the biocalatytic method to additional drug-like scaffolds...