Research
The Dassama group performs research at the interface of chemistry and biology, relying on tools of chemistry to probe and explain biological phenomena. Three research directions, described below, are ongoing.
Metabolite trafficking
Even in a relatively simple bacterium, metabolites must exist in specific locations to function properly: molecules involved in nutrient acquisition are secreted and subsequently taken up, lipids must travel to cell membranes, etc. Generally, transporter proteins mediate the trafficking of these metabolites, but at times there is poor understanding of how they function. Our research leverages bioinformatics, biochemistry, and biophysics to discover and characterize proteins that mediate the transport of bacterial metabolites. We focus on the transport of primary metabolites like lipids, which are important for cell viability, proliferation, and pathogenesis. We also study the transport of secondary metabolites and antibiotics because they are relevant to multidrug resistance mediation efforts. In this realm, our work centers around integral membrane proteins called multidrug and toxic compound efflux (MATE) pumps that have emerged as key players in MDR, as their presence enables microbes to secrete multiple antibiotics. Our research efforts are focused on determining the substrate scope and transport mechanisms for these “divergent” MATE proteins.
Bioactive natural products
Nature is replete with natural products that are used as (or inspire design of) drugs, but the rising rates of resistance to antimicrobial and anticancer compounds has heightened the need for the development of new bioactive compounds. In addition to efforts focused on the discovery and synthesis of these compounds, there is recognition that engineering of bioactive natural products could vastly expand the chemical and functional space of these molecules. Ribosomally produced and post-translationally modified peptidic natural products (RiPPs) have the potential to substantially diversify the chemical composition of known bioactive molecules in two ways: the peptides they derive from can tolerate sequence variance, and modifying enzymes can be chosen to install select functional groups. With an interest in producing new antimicrobial and anticancer compounds, the laboratory is exploiting the versatility of RiPP natural product biosynthesis. Of particular interest is an emerging class of natural products composed of thioamide-containing compounds, which comprise potent antimicrobial and anticancer agents that hold potential as therapeutics. We aim to elucidate the biosynthesis of key functional groups, identify the relevance of those functional groups to the biological activities of the natural products, and leverage that information to design and engineer more potent forms of bioactive RiPPs.
“Undruggable” protein modulation
A significant fraction of the human proteome remains “undruggable” because it comprises proteins not amenable to inhibition by small molecules. In recent years, proximity-based approaches have been used to modulate some of these proteins, primarily through degradation with proteolysis targeting chimeras (PROTACs) and molecular glues.1 PROTACs were first reported two decades ago and promised as powerful tools for biological inquiry and for advancing human health.1, 2 However, they have yet to meet their promise because a) they require small molecule ligands for proteins of interest; b) they have no tissue selectivity due to the widespread expression of recruitable E3 ligases that mediate degradation. Our research addresses these challenges.