Stanford University
Cegelski Lab
Harnessing chemistry in nature and our imagination for a brighter future.
Bold discovery and new chemistry for urgent problems in need of creative solutions.
We are intrepid explorers inspired by the challenge and need for solutions to pressing problems in human health, plant and ocean life, and sustainability. We design and deploy uniquely enabling problem-solving approaches to address these grand challenges. We have launched a collaborative antibacterial drug design program integrating synthesis, chemical biology, and mechanistic biochemistry and biophysics directed at the discovery and development of new antibacterial therapeutics targeting difficult-to-treat bacteria. We recently identified a new chemical structure never before observed in nature: phosphoethanolamine (pEtN) cellulose. We also uncovered the genetic and molecular basis for its installation, identifying a new pEtN transferase, BcsG. Common E. coli and other bacteria cloak themselves in pEtN cellulose - "a bacterial coat that is not pure cotton." This modified cellulose is prevalent among commonly studied microbes and evaded detection for decades. We are discovering dark matter that poses a challenge to discovery and analysis by conventional methods. We interrogate and map the molecular, spatial and temporal dynamics in bacterial biofilms that include pEtN cellulose as well as fascinating extracellular functional amyloid fibers termed curli and other matrix components. We explore the molecular and atomic-level assembly of cell walls, extracellular structures, and are constructing blueprints of how bacteria use these building blocks to engineer organized and dynamic architectures. We are also engaged in identifying small molecules to interfere with these processes, inhibiting cell-wall biosynthesis, amyloid assembly and polysaccharide assembly to introduce new antibacterial and antibiotic-sparing anti-virulence therapeutics for infectious diseases and neurodegenerative disease.
Bacterial Cell Walls & Biofilms
Bacteria are the found in rocks and soil particles. Bacteria symbiotically colonize plants and humans as well as coral and fish, resulting in mutual benefit to both microbe and host. Pathogenic and unwelcome bacteria colonize host tissues, leading to disease. Specific strategies have evolved in order to facilitate bacterial attachment and biofilm community formation. Biofilms are tissue-like architectures that exhibit reduced sensitivity to conventional antibiotics, host defenses, and external stresses. We must decode the chemistry and macromolecular assembly phenomena to fully understand how bacteria assemble cell-wall and biofilm structures . We are uncovering the molecular and atomic-level basis and functional implications of these phenomena to generate more complete descriptions of our ecosystems and to design and accelerate solutions to control and prevent disease.
Antibacterial Drug Discovery
Drug-resistant bacterial infections have emerged as one of the most urgent threats to public health. New antibiotics and anti-infective strategies are needed to combat resistant and difficult-to-treat bacterial populations. We are introducing new antibacterial compounds to kill both actively growing cells and slow-growing biofilm-associated bacteria and persister cells.
Our foundational studies led to the identification of agents that significantly outperform current clinically used agents and that exhibit behavior consistent with a new mode of action or dual modes of action. Our work provides the structural and conceptual basis for a broadly applicable strategy for generating new antibiotics based on facile synthetic modification of existing antibiotics.
Macromolecular and whole-cell NMR
Solid-state NMR is uniquely enabling in detecting and measuring chemistry in complex and heterogeneous materials. We uncover the molecular and atomic-level chemistry in diverse systems including bacterial biofilms, the butterfly chrysalis, plant leaves, and synthetic polymers that pose a challenge to analysis by conventional methods. The approach is powerful, versatile, and broadly applicable to diverse systems, but there are no set protocols. We design protocols to introduce isotope labels in vivo in bacteria, plants, and cellular systems, often manipulating biosynthetic pathways to take up labeled components such as amino acids, carbohydrates, or metabolites. We track these labels by various solid-state NMR detection schemes to understand how they are incorporated or transformed. The selection and development of pulsed NMR schemes depends on the problem that needs to be solved. solve outstanding problems.
Microbial Amyloids & Polysaccharides
The genomics and proteomics revolutions have been enormously successful in generating full genome sequences and in predicting and determining structures of proteins. In essence, these data provide crucial “parts lists” for biological systems. Yet, formidable challenges exist in generating complete descriptions of how the parts function and assemble into macromolecular complexes and whole-cell factories. We are inspired by the need for novel and unconventional approaches to solve these outstanding problems in biology.
We work to uncover and understand at a molecular and atomic-level how bacteria self-assemble fascinating extracellular structures and how bacteria use these building blocks to construct organized biofilm architectures. We are also engaged in identifying small molecules to interfere with these processes in a chemical genetics spirit and, more directly, for the discovery of new therapeutics.
