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Zn(II) is essential for bacterial survival and virulence. In host cells, its abundance is extremely limited, thus, bacteria have evolved transport mechanisms that enable them to take up this essential metal nutrient. Paracoccus denitrificans encodes two solute binding proteins (SBPs) – ZnuA and AztC, which are responsible for zinc acquisition from the host cells. We focus on understanding the interactions of Zn(II) and Ni(II) (zinc's potential competitor, which is a biologically relevant metal ion essential for various bacterial enzymes) with the extracellular ZnuA and AztC's loops from P. denitrificans that are expected to be possible Zn(II) binding sites. In the case of Zn(II) complexes with ZnuA outercellular loop regions, the numerous histidines act as anchoring donors, forming complexes with up to four coordinated His residues, while in the AztC region, three imidazole nitrogens and one water molecule are involved in Zn(II) binding. In Zn(II) complexes with ZnuA His-rich loop regions, so-called polymorphic binding sites are observed. The large number of available imidazoles and carboxylic side chains also strongly affects the structure of Ni(II) complexes; the more histidines in the studied peptide, the higher the affinity to bind Ni(II) and the higher the pH value at which amide nitrogens start to participate in Ni(II) binding. Additionally, for Ni(II)-ZnuA complexes, a more rare octahedral geometry is observed and such complexes are more stable than the corresponding Zn(II) ones, in contrast to what was observed in the AztC region, suggesting that the numerous histidyl and glutamic acid side chains are more tempting for Ni(II) than for Zn(II).The general strong affinity of Zn(II)-zincophore complexes is also discussed. [ABSTRACT FROM AUTHOR]

Introduction: It is recently becoming clear that there is a significant and underestimated effect of metal coordination on the antimicrobial activity of antimicrobial peptides (AMPs) - potential treasure troves for the design of novel antibiotics. Beyond any doubt, understanding the molecular mechanisms underlying these disorders is a serious challenge for modern science. Aim: The way in which metal ions affect the mode of action of AMPs is far from being understood. They may alter the charge/structure/morphology of a given AMP and therefore enhance the AMP antimicrobial potency. The aim of the project is to understand the relationship between metal coordination, thermodynamic stability, structure, morphology and antimicrobial activity of AMPs. Material and methods: Achieving the overall aim requires a complex experimental approach. Mass spectrometry, potentiometry, ITC and a fruitful combination of nMR, UV-Vis, CD and EPR spectroscopic techniques are used to describe the beautiful bioinorganic chemistry of the studied systems. Antimicrobial assays and studies on regular cell lines establish the biological potency of the novel systems. Results: We have recently elucidated the relationship between Zn(II) coordination, structural, morphological change and antifungal activity of human amylin analogues (pramlintide) and for peptides from the shepherin group (from the plant Capsella bursa pastorsis). We observe a logical sequence of phenomena, each of which is the result of the previous one: (i) Zn(II) coordinates to histidyl imidazoles, (ii) causes a structural change of the peptide, which in turn (iii) results in the formation of fibrils. Conclusions: Ultimately, this chain of structural changes has (iv) biological consequences - the Zn(II)-pramlintide and Zn(II)-shepherin complex fibrils have a strong antifungal effect. A similar effect is not observed neither in the case of free ligands, nor in the case of their complexes with Cu(II). A working hypothesis on the mode of action of such Zn(II) complexes assumes that the formed fibrils can act as needles, physically damaging the fungal cell wall or membrane. [ABSTRACT FROM AUTHOR]

Consecutive histidine repeats are chosen both by nature and by molecular biologists due to their high affinity towards metal ions. Screening of the human genome showed that transcription factors are extremely rich in His tracts. In this work, we examine two of such His-rich regions from forkhead box and MAFA proteins-MB3 (contains 18 His) and MB6 (with 21 His residues), focusing on the affinity and binding modes of Cu and Zn towards the two His-rich regions. In the case of Zn species, the availability of imidazole nitrogen donors enhances metal complex stability. Interestingly, an opposite tendency is observed for Cu complexes at above physiological pH, in which amide nitrogens participate in binding. [ABSTRACT FROM AUTHOR]

Zn(II) is essential for bacterial survival and virulence. In host cells, its abundance is extremely limited, thus, bacteria have evolved transport mechanisms that enable them to take up this essential metal nutrient. Paracoccus denitrificans encodes two solute binding proteins (SBPs) - ZnuA and AztC, which are responsible for zinc acquisition from the host cells. We focus on understanding the interactions of Zn(II) and Ni(II) (zinc's potential competitor, which is a biologically relevant metal ion essential for various bacterial enzymes) with the extracellular ZnuA and AztC's loops from P. denitrificans that are expected to be possible Zn(II) binding sites. In the case of Zn(II) complexes with ZnuA outercellular loop regions, the numerous histidines act as anchoring donors, forming complexes with up to four coordinated His residues, while in the AztC region, three imidazole nitrogens and one water molecule are involved in Zn(II) binding. In Zn(II) complexes with ZnuA His-rich loop regions, so-called polymorphic binding sites are observed. The large number of available imidazoles and carboxylic side chains also strongly affects the structure of Ni(II) complexes; the more histidines in the studied peptide, the higher the affinity to bind Ni(II) and the higher the pH value at which amide nitrogens start to participate in Ni(II) binding. Additionally, for Ni(II)-ZnuA complexes, a more rare octahedral geometry is observed and such complexes are more stable than the corresponding Zn(II) ones, in contrast to what was observed in the AztC region, suggesting that the numerous histidyl and glutamic acid side chains are more tempting for Ni(II) than for Zn(II).The general strong affinity of Zn(II)-zincophore complexes is also discussed.

Zinc is one of the most important metal nutrients for species from all kingdoms, being a key structural or catalytic component of hundreds of enzymes, crucial for the survival of both pathogenic microorganisms and their hosts. This work is an overview of the homeostasis of zinc in bacteria and humans. It explains the importance of this metal nutrient for pathogens, describes the roles of zinc sensors, regulators, and transporters, and summarizes various uptake systems and different proteins involved in zinc homeostasis-both those used for storage, buffering, and signaling inside the cell and those excreted in order to obtain Zn II from the host. The human zinc-dependent immune system response is explained, with a special focus given to 'zinc nutritional immunity', a process that describes the competition between the bacteria or fungus and the host for this metal, during which both the pathogen and host make huge efforts to control zinc availability. This sophisticated tug of war over Zn II might be considered as a possible target for novel antibacterial therapies., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)