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Laura M.K. Dassama
Assistant Professor of Chemistry
BioThe 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 uses both 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. To date, 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.
Assistant Professor of Biology
Current Research and Scholarly InterestsMy lab is interested in the relationship between cell death and metabolism. Using techniques drawn from many disciplines my laboratory is investigating how perturbation of intracellular metabolic networks can result in novel forms of cell death, such as ferroptosis. We are interested in applying this knowledge to find new ways to treat diseases characterized by insufficient (e.g. cancer) or excessive (e.g. neurodegeneration) cell death.
Associate Professor of Computer Science and, by courtesy, of Molecular and Cellular Physiology and of Structural Biology
Current Research and Scholarly InterestsMy lab’s research focuses on computational biology, with an emphasis on 3D molecular structure. We combine two approaches: (1) Bottom-up: given the basic physics governing atomic interactions, use simulations to predict molecular behavior; (2) Top-down: given experimental data, use machine learning to predict molecular structures and properties. We collaborate closely with experimentalists and apply our methods to the discovery of safer, more effective drugs.
Justin Du Bois
Henry Dreyfus Professor in Chemistry and Professor, by courtesy, of Chemical and Systems Biology
BioResearch and Scholarship
Research in the Du Bois laboratory spans reaction methods development, natural product synthesis, and chemical biology, and draws on expertise in molecular design, molecular recognition, and physical organic chemistry. An outstanding goal of our program has been to develop C–H bond functionalization processes as general methods for organic chemistry, and to demonstrate how such tools can impact the logic of chemical synthesis. A second area of interest focuses on the role of ion channels in electrical conduction and the specific involvement of channel subtypes in the sensation of pain. This work is enabled in part through the advent of small molecule modulators of channel function.
The Du Bois group has described new tactics for the selective conversion of saturated C–H to C–N and C–O bonds. These methods have general utility in synthesis, making possible the single-step incorporation of nitrogen and oxygen functional groups and thus simplifying the process of assembling complex molecules. To date, lab members have employed these versatile oxidation technologies to prepare natural products that include manzacidin A and C, agelastatin, tetrodotoxin, and saxitoxin. Detailed mechanistic studies of metal-catalyzed C–H functionalization reactions are performed in parallel with process development and chemical synthesis. These efforts ultimately give way to advances in catalyst design. A long-standing goal of this program is to identify robust catalyst systems that afford absolute control of reaction selectivity.
In a second program area, the Du Bois group is exploring voltage-gated ion channel structure and function using the tools of chemistry in combination with those of molecular biology, electrophysiology, microscopy and mass spectrometry. Much of this work has focused on studies of eukaryotic Na and Cl ion channels. The Du Bois lab is interested in understanding the biochemical mechanisms that underlie channel subtype regulation and how such processes may be altered following nerve injury. Small molecule toxins serve as lead compounds for the design of isoform-selective channel modulators, affinity reagents, and fluorescence imaging probes. Access to toxins and modified forms thereof (including saxitoxin, gonyautoxin, batrachotoxin, and veratridine) through de novo synthesis drives studies to elucidate toxin-receptor interactions and to develop new pharmacologic tools to study ion channel function in primary cells and murine pain models.
Associate Professor of Chemical Engineering
Current Research and Scholarly InterestsMy lab is deeply interested in uncovering the physical principles that underlie the construction of complex, multicellular animal life.