Advances in Understanding of the Copper Homeostasis in Pseudomonas aeruginosa

Abstract

Thirty-five thousand people die as a result of more than 2.8 million antibiotic-resistant infections in the United States of America per year. Pseudomonas aeruginosa (P. aeruginosa) is classified a serious threat, the second-highest threat category of the U.S. Department of Health and Human Services. Among others, the World Health Organization (WHO) encourages the discovery and development of novel antibiotic classes with new targets and mechanisms of action without cross-resistance to existing classes. To find potential new target sites in pathogenic bacteria, such as P. aeruginosa, it is inevitable to fully understand the molecular mechanism of homeostasis, metabolism, regulation, growth, and resistances thereof. P. aeruginosa maintains a sophisticated copper defense cascade comprising three stages, resembling those of public safety organizations. These stages include copper scavenging, first responder, and second responder. Similar mechanisms are found in numerous pathogens. Here we compare the copper-dependent transcription regulators cueR and copRS of Escherichia coli (E. coli) and P. aeruginosa. Further, phylogenetic analysis and structural modelling of mexPQ-opmE reveal that this efflux pump is unlikely to be involved in the copper export of P. aeruginosa. Altogether, we present current understandings of the copper homeostasis in P. aeruginosa and potential new target sites for antimicrobial agents or a combinatorial drug regimen in the fight against multidrug resistant pathogens.

Allostery‐driven changes in dynamics regulate the activation of bacterial copper transcription factor

“…At higher Cu(I) concentrations, inhibition of this process occurs, previously reported as a “dead‐end” state by smFRET experiments 16 . Therefore, at higher copper concentrations, alternative copper regulation mechanisms controlled by other copper regulators could reduce prolonged and elevated copper levels 2 …”

“…16 Therefore, at higher copper concentrations, alternative copper regulation mechanisms controlled by other copper regulators could reduce prolonged and elevated copper levels. 2 In our previous studies, 17,18 we also hypothesized that there is more than one Cu(I) binding site in CueR. Recently, Balogh et al 42 explored the binding of Hg(II) to CueR and suggested that the last seven residues at the Cterminal tail of CueR form a second metal ion binding site with C129 and C130 coordination.…”

“…Therefore, bacteria have evolved as highly sophisticated and complex biological processes to regulate and maintain intracellular metal homeostasis. 2,3 One of these processes is controlled by metalloregulators, which respond to metal ions and regulate the transcription of genes that protect the bacteria from metal-induced stress. 4,5 CueR, a representative member of the mercury resistance regulator (MerR) family of metalloregulators, controls expression of genes involved in copper homeostasis of bacteria.…”

The Advantages of EPR Spectroscopy in Exploring Diamagnetic Metal Ion Binding and Transfer Mechanisms in Biological Systems

“…Considering the ubiquitous presence of metals in the cell, it follows that even small errors in biometal regulation are likely to impact cell function, growth, and survival. It is, thus, of tremendous importance to understand each step in the cycle of metal uptake, usage, and clearance to achieve a fundamental understanding of the sources of metal homeostasis disruption [10][11][12].…”

“…In recent years, we have been applying EPR spectroscopy to However, in prokaryotic systems, copper regulation is more sophisticated, since such microorganisms can encounter changes in their environment. In Gram-negative bacteria, four different mechanisms regulate cellular Cu(I) (Figure 1B) [10]. The first mechanism involves proteins that export copper from the cytoplasm.…”