Acquisition of copper hyper-resistance is promoting increased bacterial survival in vivo.

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Copper is highly toxic and used as an antimicrobial by human, animal, and plant defence systems to kill invading pathogens. Consequently all bacteria have copper resistance mechanisms to counteract copper toxicity to enable survival in vivo and in the environment. But we have identified a mechanism that can give bacteria hyper-resistance to copper.The novel copper resistance mechanism (copXL) has been acquired by some strains of Staphylococcus aureus. CopX is an unusual copper efflux transporter, while CopL is a lipoprotein of unknown function. Our newly published data show that acquisition of CopXL confers resistance to extremely high levels of copper in which typical S. aureus cannot grow, and it promotes survival against the antibacterial killing by macrophages, which is part of the host's anti-bacterial defences. These results suggest that bacteria with copXL will have enhanced survival during infection. Our studies show that proteins similar to CopL and CopX, are widespread in environmental bacteria, indicating that these genes have an essential but unknown function in environmental survival. Importantly they are not usually found in pathogenic bacteria. However, these genes are now spreading to several other bacteria that are increasingly problematic in human and veterinary medicine. In S. aureus, the copXL genes are currently only found in the highly virulent and transmissible community acquired and livestock-associated methicillin resistant S. aureus (CA-, LA-MRSA) which have increased infectivity compared to typical S. aureus and they can cause disease in healthy humans with no prior exposure to healthcare settings. Additionally, copXL-like genes are spreading to several other antibiotic resistant opportunistic pathogens demonstrating increased infectivity, e.g. hospital associated vancomycin resistant Enterococcus faecium, methicillin resistant Staphylococcus haemolyticus associated with bovine mastitis, and methicillin resistant Staphylococcus pseudintermedius associated with animal infections. Our hypothesis is that acquisition of copper hyper-resistance is driving the evolution of bacteria from being opportunistic pathogens, to becoming more virulent strains that no longer need to rely on a weakened immune system to cause infection. The copXL genes are carried on mobile genetic elements that also encode genes for resistance to antibiotics. If copper hyper-resistance enhances bacterial survival by increasing survival against killing by copper, this will select for antimicrobial resistance genes on the same element as the copper resistance genes, even in the absence of other selective pressures such as antibiotics. This has major implications for our fight against antibiotic resistance and further justifies the need to understand copper hyper-resistance.We do not know how these genes confer copper hyper-resistance, nor understand the full implications of acquisition of highly efficient copper resistance mechanisms for pathogen survival and retention of antibiotic resistance in the host. Therefore the aim of this fundamental bioscience proposal is to use S. aureus as a model organism to understand the mechanisms of action of copX and copL, and the biological consequences of copper hyper-resistance acquisition. To do this we will use a multi-disciplinary approach involving biochemistry, genetics, microbiology, and in vivo models with S. aureus as a model system to: 1. Investigate the mechanisms of action of CopX and CopL. 2. Establish whether CopX and CopL enhance pathogen fitness in vivo.3. Determine the importance of copper hyper-resistance for retention of antimicrobial resistance.The results from this model system will be widely applicable for other systems where metal detoxification genes are co-encoded on mobile genetics elements with antibiotic resistance genes, and for other human infectious bacteria with copies of the copXL genes.