Associate Professor Lynette Cegelski's research is inspired by the challenge and importance of elucidating chemical structure and function in biological systems and the need for new and unconventional approaches to solve outstanding problems in biology and medicine. The Cegelski laboratory has developed a unique set of tools, particularly integrating solid-state NMR spectroscopy with biochemistry and microbiology, to determine atomic- and molecular-level detail in macromolecular assemblies, intact cells, and bacterial biofilms. Coupled with small-molecule screening and inhibitor discovery, they are driving the development of new strategies to address the global challenge of antibiotic resistance and infectious disease.
Lynette Cegelski completed her undergraduate studies in Chemistry at SUNY-Binghamton, New York (B.S. summa cum laude and Phi Beta Kappa 1998), where she participated in research to determine the microtubule-bound conformation of the anti-cancer drug Taxol by REDOR solid-state NMR. This formative experience motivated her move to Washington University to conduct her PhD training in the laboratory of Professor Jacob Schaefer, where she trained as a solid-state NMR spectroscopist (Ph.D. Biophysical Chemistry 2004). She investigated cell-wall and whole-cell systems and examined photosynthesis and photorespiration in intact leaf NMR experiments. She gained expertise in Microbiology and Infectious Disease research as a postdoctoral fellow in Molecular Microbiology at the Washington University School of Medicine, working with Professor Scott Hultgren. There, she introduced the first small-molecule inhibitors of functional amyloid assembly in bacteria. She joined the faculty of the Stanford Chemistry Department in 2008. Her work has garnered early career awards, including the Burroughs Wellcome Career Award at the Scientific Interface, the 2010 NIH Director’s New Innovator Award, and the National Science Foundation CAREER Award.
Current research in the Cegelski Lab examines bacterial cell-wall composition and, beyond the cell surface, how bacteria self-assemble extracellular structures and use these as building blocks to generate biofilm architectures. Parallel efforts involve the dissection of modes of action of newly discovered antimicrobials and anti-virulence compounds. Lab members employ biophysical and biochemical tools, develop new assays and protocols, and design new strategies using solid-state NMR spectroscopy to examine assemblies such as amyloid fibers, bacterial cell walls, and biofilms. Recent discoveries have emerged from work with E. coli, S. aureus, Vibrio cholerae, and Pseudomonas aeruginosa. Translationally, small-molecule screening efforts have identified biofilm inhibitors that are being tested as potential inhibitors of pathogenesis in vivo.
The laboratory recently discovered that E. coli produces a chemically modified form of cellulose that contributes to the integrity of the biofilm extracellular matrix. Its presence evaded detection through decades of research on bacterial cellulose due to the challenges associated with using solution-based methods to interrogate biomass breakdown products. The laboratory is pursuing several avenues related to manipulations and applications of this new cellulosic material.
Additional targets of study include functional amyloid fibers termed curli and the mechanism by which bacteria use curli together with cellulose to construct biofilm architectures. The curli system is notable as a dedicated amyloid-assembly machinery and inhibitors of curli assembly may also hold promise as inhibitors of amyloids associated with human disease.
Collectively, the Cegelski Research Program is positioned at the scientific interface of Chemistry, Biology, and Engineering and is revealing new bacterial structures, new anti-infective targets, and inhibitors of bacterial adhesion and biofilm formation.
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