Background:The multicopper oxidase CueO allows Escherichia coli to survive in aqueous solutions with a high copper concentration. Results: Cu(I) and Ag(I) ions coordinate to a flexible, methionine-rich sequence. Conclusion:The methionine-rich insert and a substrate-binding site ensure that only Cu(I) is oxidized. Significance: Understanding how bacteria survive in the presence of normally toxic concentrations of metal ions may lead to better antibacterial agents.

As a trace element copper has an important role in cellular function like many other transition metals. Its ability to undergo redox changes [Cu(I) ↔ Cu(II)] makes copper an ideal cofactor in enzymes catalyzing electron transfers. However, this redox change makes copper dangerous for a cell since it is able to be involved in Fenton-like reactions creating reactive oxygen species (ROS). Cu(I) also is a strong soft metal and can attack and destroy iron-sulfur clusters thereby releasing iron which can in turn cause oxidative stress. Therefore, copper homeostasis has to be highly balanced to ensure proper cellular function while avoiding cell damage.Throughout evolution bacteria and archaea have developed a highly regulated balance in copper metabolism. While for many prokaryotes copper uptake seems to be unspecific, others have developed highly sophisticated uptake mechanisms to ensure the availability of sufficient amounts of copper. Within the cytoplasm copper is sequestered by various proteins and molecules, including specific copper chaperones, to prevent cellular damage. Copper-containing proteins are usually located in the cytoplasmic membrane with the catalytic domain facing the periplasm, in the periplasm of Gram-negative bacteria, or they are secreted, limiting the necessity of copper to accumulate in the cytoplasm. To prevent cellular damage due to excess copper, bacteria and archaea have developed various copper detoxification strategies. In this chapter we attempt to give an overview of the mechanisms employed by bacteria and archaea to handle copper and the importance of the metal for cellular function as well as in the global nutrient cycle.

The presence of metal resistance determinants in bacteria usually is attributed to geological or anthropogenic metal contamination in different environments or associated with the use of antimicrobial metals in human healthcare or in agriculture. While this is certainly true, we hypothesize that protozoan predation and macrophage killing are also responsible for selection of copper/zinc resistance genes in bacteria. In this review, we outline evidence supporting this hypothesis, as well as highlight the correlation between metal resistance and pathogenicity in bacteria. In addition, we introduce and characterize the Bcopper pathogenicity island^identified in Escherichia coli and Salmonella strains isolated from copper-and zinc-fed Danish pigs.

Metals and metalloids have been used alongside antibiotics in livestock production for a long time. The potential and acute negative impact on the environment and human health of these livestock feed supplements has prompted lawmakers to ban or discourage the use of some or all of these supplements. This article provides an overview of current use in the European Union and the United States, detected metal resistance determinants, and the proteins and mechanisms responsible for conferring copper and zinc resistance in bacteria. A detailed description of the most common copper and zinc metal resistance determinants is given to illustrate not only the potential danger of coselecting antibiotic resistance genes but also the potential to generate bacterial strains with an increased potential to be pathogenic to humans. For example, the presence of a 20-gene copper pathogenicity island is highlighted since bacteria containing this gene cluster could be readily isolated from copper-fed pigs, and many pathogenic strains, including O104:H4, contain this potential virulence factor, suggesting a potential link between copper supplements in livestock and the evolution of pathogens.

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