Natural Products: From Discovery to Therapeutic Applications

Numerous studies with varying degrees of statistical power have found correlations between the composition of the bacterial population in the human gut microbiome and disease states. But the molecules and mechanism(s) connecting a dysbiotic microbiome to a specific disease are generally unknown. In an attempt to address this gap, we undertook a series of screens to link bacterial metabolites with diseases like type 1 diabetes (T1D) and inflammatory bowel disease (IBD). We focused on primary drivers of inflammation like TNFα (tumor necrosis factor alpha) produced by dendritic cells. The talk will describe our screening logic, the selection of candidate bacterial strains, the discovery of the small molecule regulators of cytokine production, their structures and biosynthesis, and inflammatory mechanism.

Plants are some of the best chemists on the planet and produce an impressive array of small molecules. We are inspired by the fact that humans have become extraordinarily reliant on plant-derived molecules for food, medicine, and energy. However, remarkably little is known about how plants make these molecules, limiting our ability to engineer and optimize plant metabolic pathways. New plant genome sequences and synthetic biology tools have enabled three research areas under investigation in my lab: 1) Identifying the minimum set of enzymes required to make known plant-derived molecules and non-natural derivatives through metabolic engineering, and 2) discovering new molecules from plants, and 3) developing new strategies to enhance plant fitness. In this talk, I will describe some of our recent efforts to accelerate the discovery of complete plant pathways for known and novel molecules, not only in the model plant Arabidopsis but also in non-model plants.

The human body is colonized by trillions of microorganisms that exert a profound influence on human biology, in part by providing functional and biosynthetic capabilities that extend beyond those of host cells. In particular, there is growing evidence linking chemical processes carried out by the human gut microbiome to disease. However, we still do not understand the vast majority of the molecular mechanisms underlying this phenomenon. Major obstacles faced in surmounting this knowledge gap include the difficulty linking functions associated with the human gut microbiome to specific microbial enzymes and the challenge of controlling these activities in complex microbial communities. This talk will discuss my lab's efforts to characterize gut microbial metabolic activities that are linked to colorectal cancer, including a genotoxin called colibactin. Gaining a molecular understanding of cancer-associated gut microbial activities will not only help to elucidate the mechanisms by which these organisms contribute to carcinogenesis but should also enable efforts to treat and prevent disease by manipulating this microbial community.​

The Nomura Research Group is focused on redefining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “druggable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel druggable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel druggable hotspots for undruggable protein targets and pathways. Our second research area focuses on discovering and exploiting unique druggable modalities accessed by natural products. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation and to discover new induced proximity-based therapeutic modalities.Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.

The nemamides are produced by two megaenzymes, PKS-1 and NRPS-1, in two essential neurons in the nematode C. elegans and promote survival of the worm during starvation.  These natural products are quite remarkable as they represent the first hybrid polyketide-nonribosomal peptides to be discovered in an animal species.  Our lab is studying how the biosynthesis of these natural products is coordinated in the context of a complex animal system in order to influence underlying physiology.  We have used CRISPR-Cas9 to sequentially inactivate enzymatic domains in PKS-1 and NRPS-1 in order to map the assembly-line process that leads to the nemamides.  Furthermore, we have identified multiple additional enzymes, encoded by genes distributed throughout the genome, that function in trans in nemamide biosynthesis.   Our work reveals a number of noncanonical features to nemamide biosynthesis, provides new insights into the trafficking of biosynthetic intermediates, and shows how nemamide production is coupled to the production of other signaling molecules in the worm.

Bacteria produce many small molecules that possess unique structures and potent antimicrobialactivity. It is often unclear how these molecules impart their activity. I will discuss our work on understanding the mode of action for the broad-spectrum, dithiolopyrrolone antibiotics. We showed that this family of natural products inhibits metal-dependent enzymes in cells via metal-ion chelation. The cyclic ene-disulfide of the dithiolopyrrolone exhibits unusual redox chemistry and is essential for activity. I will also describe our efforts on elucidating the mode of action of the natural product thiomarinol A. Thiomarinol A is a hybrid antibiotic that combines the dithiolopyrrolone and a close analog of mupirocin, the latter of which is used to treat methicillin-resistant Staphylococcus aureus. Our work identified novel antimicrobial mechanisms and could help discover and design antibiotics that can avoid or overcome resistance.