Copper (Cu) has been used to sterilize wounds and drinking water. Normal valence states of copper include Cu1+ and Cu2+. Cu is an essential nutrient in humans (in small, nontoxic amounts). The [attached] article describes how Cu can be toxic to bacteria. Cu is becoming increasingly used by hospitals to decrease microbial burden on touch surfaces, especially in these days of increasing frequencies of resistance to biological antibiotics. Can bacteria become resistant to Cu..?? This is a story of gene-environment interactions: Cu is the environmental signal; and, of course, genes can be up- and down-regulated, in response to this signal.
The human innate immune system uses Cu to kill invading microorganisms; upon challenge with bacteria, macrophages accumulate Cu within their phagosomes [vacuoles (enclosed within a part of the cell membrane) in a cell’s cytoplasm, which collects extraneous particles], where it may synergize with reactive oxygen species (ROS; produced by NADPH oxidase) to increase killing. Staphylococcus aureus is a public health concern, worldwide. S. aureus causes numerous infection types — ranging from skin and soft tissue infections to more severe and life-threatening diseases, such as pneumonia, osteomyelitis (infection of the bone), and bacteremia (bacteria in the bloodstream, which can lead to serious sepsis). Methicillin-resistant S. aureus (MRSA) infections have become more prevalent in community settings; this epidemic is widely attributed to the spread of the USA300 clone of S. aureus.
As complications associated with antibiotic resistance have intensified, Cu is attracting attention as an antimicrobial agent. Recent studies have shown that copper surfaces can decrease microbial burden. Not surprisingly, microbes have evolved mechanisms to tightly control intracellular Cu pools and protect against Cu toxicity. Authors [see attached article] identified two genes, copB and copL, encoded within the S aureus arginine-catabolic mobile element (ACME), that had been hypothesized to function in Cu homeostasis. Supporting this hypothesis, mutational inactivation of either the copB or copL gene increased Cu sensitivity.
Authors found that the copB/copL genes (arranged in tandem) are co-transcribed and that their transcription is increased — during copper stress. Transcription of the copB/copL genes is also increased in a strain in which csoR, encoding a Cu-responsive transcriptional repressor, was mutated. Moreover, copB displayed genetic synergy with another gene, copA, suggesting that CopB functions in Cu export (moving Cu out of the cell). Authors discovered that CopL functions independently of CopB or CopA in Cu toxicity protection — and that CopL from the S. aureus clone USA300 is a membrane-bound and surface-exposed lipoprotein that binds as many as four cuprous (Cu1+) ions.
Comparing solution nuclear magnetic resonance (NMR) structures of the homologous Bacillus subtilis CopL protein, together with phylogenetic analysis and chemical-shift perturbation experiments, authors identified conserved residues potentially involved in Cu1+ coordination. The solution-NMR structure also revealed a novel Cu-binding architecture. Of note, a CopL variant with defective Cu1+ binding did not protect against Cu toxicity in vivo. Taken together, these findings indicate that the ACME-encoded CopB and CopL proteins are additional factors, used by the highly successful S. aureus USA300 clone, to suppress Cu toxicity in this serious pathogen.
J Biol Chem 2019; 294: 4027-4044