The Fisher lab investigates how bacteria respond and adapt to changes in their environments. We use a variety of complementary approaches spanning X-ray crystallography, bioinorganic chemistry, biochemistry, biophysics, and microbiology to pursue two primary research areas, described below. Our longer-term goals for both of these research areas are to harness our findings to develop novel treatments for bacterial infections.

1. Copper recognition, acquisition, and use by Gram positive bacteria

Cu is one of the most ancient antimicrobial tools, but there are still major gaps in the fundamental understanding of how bacteria handle this transition metal. Significant research efforts have greatly advanced the current knowledge of how microorganisms remove Cu when it is in excess. More recently, however, Cu- dependent proteins have also been found to reside in the cytosol, suggesting that intracellular Cu may be an important component of bacterial life. We hypothesize that Cu uptake is regulated by Cu-dependent transcriptional repressors and the proteins under their control. To investigate this question, we are studying the structure and function of proteins that have been implicated in these processes.

2. Enzyme specificity for a subclass of bacterial kinases

Bacteria can mount responses to different types of stimuli by using signal transduction pathways that frequently include one or more kinases that phosphorylate their substrates. A subclass of these enzymes that are found across bacterial phylogeny carry out distinct chemistry from most of their bacterial counterparts. What features of these enzymes drives their specificity for their preferred substrates? We hypothesize that structural variations are important for conferring distinct substrate specificity and kinetics and can be targeted by small molecule inhibitors. To investigate this question, we are studying the biochemistry, structure, and biological roles of a panel of enzyme-substrate pairs.

Oriana double majored in Biochemistry and English at Brandeis University, where her interest in structural biology was sparked while working in Prof. Greg Petsko and Prof. Dagmar Ringe’s joint laboratory. After graduating from Brandeis, she went on to receive her PhD from Yale University. As a graduate student, she worked in Prof. Titus Boggon’s laboratory where she studied the structure and function of the protein cerebral cavernous malformations 2 (CCM2), a protein in which mutations have been implicated in neurovascular disease. She subsequently completed a postdoctoral fellowship at Northwestern University, where she worked in Prof. Amy Rosenzweig’s laboratory studying copper-dependent proteins produced by methane-oxidizing bacteria. Before coming to Wesleyan, she was on the faculty of the chemistry department at Lehigh University.