The ability of metal ionophores to induce cellular metal hyperaccumulation endows them with potent antimicrobial activity; however, the targets and mechanisms behind these outcomes are not well understood. This work describes the first utilization of proteome-wide measurements of protein folding stability in combination with protein expression level analysis to identify protein targets of copper, thereby providing new insight into ionophore-induced copper toxicity in . The protein folding stability analysis employed a one-pot protocol for ulse roteolysis (PP) in combination with a emi-ryptic peptide nrichment strategy for roteolysis rocedures (STEPP) to generate stability profiles for proteins in cell lysates derived from exposed to copper with and without two ionophores, the antimicrobial agent pyrithione and its β-lactamase-activated prodrug, PcephPT.
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