Megan M McEvoy

Research Interests

My research is focused on understanding how metals are maintained at appropriate levels within cells. I am particularly interested in elucidating the mechanisms of systems that drive the transport of metals across membranes and their regulatory systems. These macromolecular machines are utilized by cells to maintain the delicate balance between having sufficient metals for cellular needs, but avoiding the toxic effects of overexposure. Progress in understanding of the mechanisms of these types of systems will aid in understanding the fundamental principles of energetic coupling and control in macromolecular machines and also will lead to practical applications through regulation of these systems. Prior analysis has revealed many of the genes encoding proteins involved in metal sensing and export, but further progress requires an understanding of the molecular details of protein function. The McEvoy lab has focused on biochemical and structural studies to achieve these objectives. Molecular Mechanisms of Microbial Metal Homeostasis and Resistance. Intracellular levels of metals need to be carefully controlled for proper cellular function. For example, though copper is required at the active site of many essential enzymes, excess copper can be toxic, due to coordination with random functional groups as well as through generation of radical species. Because metals are generally inexpensive and show toxic effects over a broad spectrum of organisms, metals are in widespread use to control microbial growth in a variety of clinical and environmental applications. However, resistance systems that allow organisms to survive under excess environmental metal concentrations reduce the efficacy of metals as biocides. One category of metal resistance systems are the CBA transporters, which form a large protein complex spanning two membranes and utilize the transmembrane proton gradient to pump metals out of the cell. The similarity of these efflux systems to multidrug resistance systems compels a better understanding of their mechanisms due to the threat that multidrug resistant organisms pose to human health, as well as in the interests of the continued use of metal as broad spectrum biocides. My research aims to understand the biochemical mechanisms of microbial metal efflux systems. Using NMR spectroscopy, X-ray crystallography and other biochemical techniques coupled with in vivo assays, we are seeking to determine the functions of the proteins involved, as well as to obtain a molecular understanding of their specificity and regulation. The regulatory systems that control expression of the transporters that confer resistance are also under investigation. We seek to understand how metals activate these response proteins, and how metal discrimination takes place, through structural and biochemical investigations.At the conclusion of these studies, we will have the tools to understand the microbial response to metal biocides and provide strategies for their effective use in controlling bacterial infections in human populations.