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Copper is an essential metal which is used as a cofactor in several enzymes and is required for numerous essential biochemical reactions. However, free copper ions can be toxic to cellular systems if the intracellular concentration is not tightly regulated. In this study we show thatStaphylococcus aureuscopper resistance is not the same in every staphylococcal isolate, but in fact varies considerably between clinical strains. Hyper-copper-resistance was shown to be due to the carriage of an additional plasmid-encoded copper homeostasis mechanism,copBmco. This plasmid can be transferred into the copper-sensitiveS. aureusNewman to confer a hyper-copper-resistant phenotype, showing that copper resistance has the potential to spread to otherS. aureusstrains. This is the first time that plasmid-encoded copper resistance has been reported and shown to be transferable between pathogenic bacteria isolated from humans. A homologue of theBacillussubtilisandMycobacterium tuberculosisCsoR regulators was identified inS. aureus. TheS. aureus csoRgene is conserved in all sequencedS. aureusgenomes and was found to be copper-induced and transcribed along with two downstream genes: a putative copper chaperone (csoZ) and a hypothetical gene. Mutational and complementation studies showed that unlike other homologues, theS. aureusCsoR negatively regulates both chromosomal and plasmid-encoded copper homeostasis mechanisms in response to excess-copper conditions.