It has recently emerged that host innate immune cells use copper to kill invading bacteria. To avoid copper stress, most bacteria possess copper tolerance genes that encode an array of proteins for efflux, trafficking (chaperones), and storage. These genes contribute to bacterial virulence, and they are usually transcriptionally controlled by a copper sensor.
The genes encoding for the copper sensor (cueR) and copper efflux pump (copA) are typically encoded on the chromosome as a divergent but contiguous operon. In E. coli, cueR and copA are separated by two additional genes, ybaS and ybaT, which confer glutamine (Gln)-dependent acid tolerance and contribute to glutamate (Glu)-dependent acid resistance system. We have recently shown that E. coli alters its metabolism and harness Gln to suppress the effects of copper toxicity. Given the abundance of Gln in the host systemic circulation, our work provides an insight into the ways in which bacterial pathogens can adapt and survive host-imposed antibacterial strategies.
Extensive in silico searches have identified Neisseria sp. (N. gonorrhoeae is listed by the WHO amongst the highest priority global pathogens) as one exception to the dogma of bacterial copper homeostasis. A recognisable copper sensor is notably missing from this organism and there is no identifiable system for copper trafficking. In collaboration with the Waldron Group (Newcastle University, UK) and Kobe Group (University of Queensland, Australia), we aim to identify and characterise components of this unprecedented system using cross-disciplinary methods across the biosciences.
At the fundamental biochemical level, copper poisons bacteria by displacing other metal ions in metalloproteins. However, precisely which protein is targeted is not always predictable – it varies with the organism and the consequence on pathogenesis is not immediately obvious. Together with the Walker Group (University of Queensland, Australia) and the Lowe Group (Newcastle University, UK), we aim to uncover the mechanisms of bacterial copper stress using the Gram-positive pathogen S. pyogenes as our model organism.