- This event has passed.
Department Seminar: Breaking down Bacterial Cell Walls to Understand Inflammation
April 26, 2018 @ 2:30 pm - 3:30 pm
Breaking down Bacterial Cell Walls to Understand Inflammation
Professor Catherine Grimes
University of Delaware
Thursday, April 26, 2018
2:30 PM – 3:30 PM
Natural Sciences II, Room 4201
Bacterial cell wall biosynthesis ranks among the top targets for antibiotics. The bacterial cell wall, a polymer of carbohydrate and peptides, makes an excellent antibiotic target for two reasons: (1) it is essential for bacteria and (2) humans do not have bacterial cell walls – thus the drugs do not harm human cells. In addition to serving as a target for antibiotics, the human innate immune system uses the bacterial cell wall as a molecular calling card to recognize their presence and subsequently generate the appropriate immune response. We are interested in understanding how the bacterial cell wall is processed both by bacteria and the human host and propose new methods and tools for the characterization of this important polymer. Both commensal and pathogenic bacteria are believed to produce peptidoglycan fragments and misrecognition can lead to the development of inflammatory bowel disease (IBD), such as Crohn’s disease (CD), asthma and gastrointestinal (GI) cancers. Importantly, a long-standing debate around the biological relevance of the immunoactive synthetic fragment muramyl dipeptide (MDP) remains unclear due to a lack of NAM-based probes. We hypothesize that there are unidentified enzymatic targets and bacterial cell wall fragments that will be useful in the design of novel antibiotics and anti-inflammatory therapies.
We have taken a two-pronged approach towards testing this hypothesis. From the small molecule side, we have established an in vitro assay, which allows us to assess the affinity of Nod2, an innate immune receptor that binds to bacterial cell wall fragments. This assay has allowed us to tease apart binding from activation and we have begun to derive rules for molecular recognition by intracellular innate immune receptors. In addition, we have developed a robust synthetic method to readily access a library of bacterial cell wall derivatives. These derivatives will be used as affinity reagents to capture both human and bacterial enzymes that are responsible for bacterial cell wall processing. From the larger polymer side, we have embedded carbohydrates with small modifiable tags into the bacterial cell wall. We developed a method to label the NAM glycan backbone of E. coli, P. putida, and B. subtillis in whole cells. The results reveal fundamental architectural details of the glycan chains of the peptidoglycan, and further enable us to track the engulfment and breakdown of bacteria by macrophages, ultimately revealing a peptidoglycan digestion mechanism for invasive bacteria.
Schaefer AK, Melnyk JE, Baksh MM, Lazor KM, Finn MG, Grimes CL. Membrane Association Dictates Ligand Specificity for the Innate Immune Receptor NOD2 ACS Chem Biol. 12, 2216-2224 (2017)
Liang H, DeMeester KE, Hou CW, Parent MA, Caplan JL, Grimes CL. Metabolic labeling of the carbohydrate core in bacterial peptidoglycan and its applications. Nat Commun. 8, 15015 (2017)
About Dr. Catherine Grimes
Catherine Leimkuhler Grimes was born in 1978 in Camden, New Jersey and obtained a BS in Chemistry in 2001 from Villanova University, where she conducted undergraduate research in the laboratories of Professor Eduard Casillas. She obtained her masters in 2003 from Princeton University and PhD from Harvard University in 2006; her entire graduate work was conducted under the guidance of Professor Daniel E. Kahne, which focused on synthesizing glycopeptides to combat antibiotic resistance. She closely collaborated with Drs. Suzanne Walker and Christopher Walsh thereby broadening her investigation of vancomycin resistance to the interface of chemistry and biology. From 2006-2011, Catherine was a HHMI and Cancer Research Institute Postdoctoral fellow in the laboratories of Erin O’Shea (Harvard University, Molecular and Cellular Biology) and Daniel Podolosky (Massachusetts General Hospital). During her postdoctoral studies she took her chemical intuition and expanded her biological skillset to uncover problems at the molecular and cellular biology levels while delineating the immune system and cell signaling.
Catherine joined the University of Delaware’s Chemistry and Biochemistry Department as an Assistant Professor of Chemistry and Biochemistry in 2011. She was appointed a joint faculty in the Department of Biological Sciences in 2012. Her research program focuses on the development and chemical synthesis of small molecule carbohydrate probes that mimic intermediates of bacterial cell wall biosynthesis and bacterial-host immune recognition. Dr. Leimkuhler Grimes is nationally recognized as a young leader in the field of chemical biology, as she has received numerous awards including a Pew Biomedical Scholars Award, a Cottrell Scholar, and an Alfred P. Sloan Research Fellowship. She received the American Chemical Society’s Infectious Disease Young Investigator Award and was named the Mangone Young Investigator Award from the Unidel Foundation. She is the co-director of a NIH funded graduate program at the interface of chemistry and biology and the faculty mentor to a dynamic group of undergraduate STEM majors, “The Scientistas”.