The Dassama laboratory at Stanford performs research directed at understanding and mitigating bacterial multidrug resistance (MDR). Described as an emerging crisis, MDR often results from the misuse of antibiotics and the genetic transfer of resistance mechanisms by microbes. Efforts to combat MDR involve two broad strategies: understanding how resistance is acquired in hopes of mitigating it, and identifying new compounds that could serve as potent antibiotics. The successful implementation of both strategies relies heavily on an interdisciplinary approach, as resistance mechanisms must be elucidated on a molecular level, and formation of new drugs must be developed with precision before they can be used. The laboratory will use these strategies to contribute to current MDR mitigation efforts.
One area of research involves integral membrane proteins called multidrug and toxin efflux (MATE) pumps that have emerged as key players in MDR because their presence enables bacteria to secrete multiple drugs. The genes encoding these proteins are present in many bacterial genomes. However, the broad substrate range and challenges associated with membrane protein handling have hindered efforts to elucidate and exploit transport mechanisms of MATE proteins. Many of the substrates identified for MATE proteins are small and ionic drugs, but recent reports have implicated these proteins in efflux of novel natural product substrates. The group’s approach will focus on identifying the natural product substrates of some of these new MATE proteins, as well as obtaining static and dynamic structures of the proteins during efflux. These efforts will define the range of molecules that can be recognized and effluxed by MATE proteins and reveal how their transport mechanisms can be exploited to curtail drug efflux.
Another research direction involves the biosynthesis of biologically active natural products. Natural products are known for their therapeutic potential, and those that derive from modified ribosomal peptides are an important emerging class. These ribosomally produced and post-translationally modified peptidic (RiPP) natural products have the potential to substantially diversify the chemical composition of known molecules because the peptides they derive from can tolerate sequence variance, and modifying enzymes can be selected to install specific functional groups. With an interest in producing new antimicrobial and anticancer compounds, the laboratory will exploit the versatility of RiPP natural product biosynthesis. Specifically, efforts in the laboratory will revolve around elucidating the reaction mechanisms of particular biosynthetic enzymes and leveraging that understanding to design and engineer new natural products with desired biological activities.