2018 New Investigator Grant
Joseph Cotruvo, Ph.D. Assistant Professor, Department of Chemistry, Pennsylvania State University
Illuminating Transition Metal Homeostasis in Pathogenic Bacteria Through Fluorescent Sensors
Abstract
Life is largely organic – the human body is >95% carbon, oxygen, hydrogen, and nitrogen – but the inorganic constituents of life (primarily, metals) play outsized roles. The enzymes that catalyze Nature’s most challenging and important reactions, such as photosynthesis, nitrogen fixation, and synthesis of the building blocks of DNA, all require metal ions. For example, one of the most important metals used in biology is iron, which is required by all but a handful of organisms for myriad cellular functions – for example, red blood cells are red because of the iron ion that is a component of a molecule called heme, inserted into a protein, hemoglobin; the iron ion binds and transports oxygen throughout the body. Given the ubiquitous importance of iron and other transition metals in biology, one of the major mechanisms by which humans combat invading pathogens is by attempting to control the pathogens’ access to the metals that they need to survive. As a step toward better understanding the role of transition metals in pathogenesis, we have begun to develop molecular imaging tools that will allow us to determine the size, localization, and dynamics of metal pools in live bacteria and to identify genes involved in regulating these factors in normal and disease states. In particular, we will use Nature’s platforms for metal sensing and engineer them into new fluorescent tools to study metal ions in live cells. Our preliminary results have uncovered a potentially novel way that these critical nutrients are regulated in certain pathogenic bacteria, and this proposal also aims to further elucidate this mechanism. Through application of our tools and utilization of an array of more traditional biochemical methods, we will begin to illuminate unanticipated ways that transition metals contribute to infectious disease, with the goal of uncovering novel and unique avenues for therapeutic intervention.