Dr. Erin E. Carlson | Smith Professor of Chemistry, University of Minnesota
Professor bio:
Erin E. Carlson (she/her) received her B.A. at St. Olaf College (Northfield, MN) in 2000. She went on to graduate studies funded by the NIH Predoctoral Biotechnology Training Program at the University of Wisconsin – Madison and earned a Ph.D. in organic chemistry in 2005 under the direction of Professor Laura L. Kiessling. Her graduate career focused on the design and synthesis of mechanistic probes and inhibitors for carbohydrate-binding proteins, concentrating on the study of UDP-galactopyranose mutase (UGM), an enzyme involved in cell wall biosynthesis of Mycobacterium tuberculosis. Subsequently, Dr. Carlson was awarded an American Cancer Society Postdoctoral Fellowship for studies at The Scripps Research Institute with Professor Benjamin F. Cravatt. Carlson and Cravatt developed a global metabolite profiling strategy that utilizes chemoselective probes to enable enrichment and profiling of metabolites from complex biological systems. This technology, referred to as Metabolite Enrichment by Tagging and Proteolytic Release (METPR), facilitates the rigorous characterization of biochemical pathways through their most sensitive reporter, endogenous small molecules. In 2007, Dr. Carlson received an NIH Pathway to Independence Award (K99/R00) and joined the faculty at Indiana University in 2008. In the summer of 2014, she joined the faculty in the Chemistry Department at the University of Minnesota and was appointed as a Graduate Faculty member of the Department of Medicinal Chemistry, the Department of Biochemistry, Molecular Biology and Biophysics and the graduate program in Biomedical Informatics and Computational Biology in 2015. She also joined the Department of Moelcular Pharmacology and Therapeutics in 2020. In 2021, Dr. Carlson was promoted to the endowed position of Smith Professor of Chemistry.
Abstract:
Bacterial two-component systems (TCSs) are crucial for the translation of complex molecular environments into microbial action. Prokaryotes have 20-120 distinct TCSs per organism and although ~50,000 TCS proteins have been identified from genomic sequences, most have not been characterized. In particular, much remains to be learned about the TCSs that control pathogenesis and virulence in numerous organisms. This knowledge is critical as the TCSs may serve as new antibacterial targets, which are desperately needed. We have focused on P. aeruginosa infections, which have reached a “critical” threat status making novel therapeutic approaches required. We have demonstrated the potential of TCS inhibition with benzothiazole- based molecules that perturb multiple virulence pathways in the burn wound P. aeruginosa isolate, PA14. While phenotypic investigations show promising decreases in multiple virulence mechanisms, we sought to obtain a deeper mechanistic understanding of their function through the combined use of RNA-Seq, to assess global transcript regulation, and activity-based protein profiling, to identify the direct protein targets of our devised inhibitors. These data indicate significant decreases in the expression of genes associated with motility pathways such as Type IV pilius production, flagellar proteins, and chemotaxis. We have also demonstrated efficacy in Salmonella enterica serotype Typhimurium and Enterobacterales, including resensitization to polymyxin antibiotics. These promising results establish that blocking of bacterial signaling in Gram-negative bacteria has dramatic consequences on virulence behaviors and great potential for future therapeutic development.
