Person:

Sirasani, Gopal

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

Organic chemists and metabolic engineers use largely orthogonal technologies to construct essential small molecules like pharmaceuticals and commodity chemicals. While chemists have leveraged the unique capabilities of biological catalysts for small molecule production, metabolic engineers have not likewise integrated reactions from organic synthesis with the metabolism of living organisms. Here we report a method for alkene hydrogenation that utilizes a palladium catalyst and hydrogen gas generated directly by a living microorganism. This biocompatible transformation, which requires both catalyst and microbe and can be used on a preparative scale, represents a new strategy for chemical synthesis that combines organic chemistry and metabolic engineering.

The cylindrocyclophanes are a family of natural products that share a remarkable paracyclophane carbon scaffold. Using genome sequencing and bioinformatic analyses, we have discovered a biosynthetic gene cluster involved in the assembly of cylindrocyclophane F. Through a combination of in vitro enzyme characterization and feeding studies, we have confirmed the connection between this gene cluster and cylindrocyclophane production, elucidated the chemical events involved in initiating and terminating an unusual type I polyketide synthase (PKS) assembly line, and discovered that macrocycle assembly involves functionalization of an unactivated carbon center.