Abstract 1547 Why is copper toxic, and how can we direct it for benefit?

Normal and pathogenic cells require a menu of metal nutrients for optimal growth, but also strategies to mitigate toxicity associated with misregulated or excessive levels of metals, including copper. Cells adjust copper homeostasis mechanisms depending on cell type, local growth conditions, and in response to stress. These situations present opportunities to manipulate cellular copper as a therapeutic strategy against several diseases, including infection. But what are the targets and mechanisms of copper toxicity? Here I will present approaches we are using to interrogate cellular proteomes for protein targets of copper toxicity. By combining conventional protein expression level analysis with measurements of protein folding stability changes across cellular proteomes, our data reveal proteins involved in multiple biological processes directly disrupted by changes in copper status induced by pharmacological manipulation. More broadly in the context of infectious diseases, we are using these approaches in combination with other chemical and imaging methods to elucidate the mechanisms by which small molecules and peptides leverage copper-dependent processes to effect antimicrobial outcomes. This work was supported by the US National Institutes of Health (R01GM145035).