Gallium as an Antibacterial Agent: A DFT/SMD Study of the Ga<sup>3+</sup>/Fe<sup>3+</sup> Competition for Binding Bacterial Siderophores

Kircheva, Nikoleta; Dudev, Todor

doi:10.1021/acs.inorgchem.0c00367

Cited by 42 publications

(20 citation statements)

References 67 publications

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“…Ab initio and DFT calculations are very trustworthy in reproducing geometries in biological systems and revealing the thermodynamic interactions between the building components of the studied systems. − The main limiting factor, however, is the number of basis functions that can be computed. A widespread methodology in this case is the use of models for the amino acid residues that interact with metal cations in the studied centers in a direct manner. ,,− Notably, the interactions between amino acid side chains and metal cations are electrostatic in nature (charge–charge or dipole–charge type of interactions) and are localized almost entirely in the side-chain head. The hydrocarbon linker between the headgroup and the protein backbone has a negligible contribution to the overall energetics of the metal–amino acid interaction.…”

Section: Computational Methodologymentioning

confidence: 99%

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

et al. 2020

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Metal cations are required for the proper function of a great amount of biological processes, as they are indispensable cofactors participating in up to 40% of the active sites of the proteins. In the case of some diseases, however, metal cations could exhibit a dual function. As an example, the role of the zinc cation in the development of Retinitis pigmentosa could be given. Experimental works indicate the loss of thermostability of the rhodopsin protein, subjected to the combination oftypical for the diseasemutations and increased quantity of Zn 2+ . Two structural networks in the intradiscal domain surrounding His100 and His195 are supposed to be susceptible to pathophysiological changes in trace metal concentrations. From a thermodynamic point of view, it is of particular interest to decipher the foundations of the observed outcome, as well as to closely characterize the intimate interactions between the "native" cation and the building amino acid residues of the studied centers. Therefore, the powerful, but fundamentally limited, tools of computational chemistry were applied on simplified models of rhodopsin metal centers in order to shed light on the following aspects: (1) what is the preferred geometry of the Zn 2+ -containing complexes with the amino acid ligands from the binding pockets; (2) what is the role of the mutations for the interactions between Zn 2+ and the examined centers; (3) could other divalent cations such as Ca 2+ and Cu 2+ substitute for the native zinc; (4) how does the dielectric constant of the environment affect the processes? The obtained results illuminate some aspects of the zinc coordination to amino acid residues and zinc biochemistry related to the presumed pathogenesis of Retinitis pigmentosa.

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Section: Computational Methodologymentioning

confidence: 99%

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

et al. 2020

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“…Although it is exclusively a theoretical approach to the problem, the presented study is solidly based on experimental data provided in literature. This particular combination of theory and experiment has previously been found reliable when the focus is on delineating governing factors of the utmost importance between native and alien metal species in biological systems [ 29 , 30 , 31 , 32 , 33 , 34 ]. In order to more thoroughly establish the extent to which Ag + co-opts endogenous copper and where, alternatively, it is handled uniquely, we modeled the reactions of competition for binding constructs built by different types and numbers of amino acid residues, known to take part in the metal-binding centers in T1Cu proteins.…”

Section: Introductionmentioning

confidence: 98%

Cu+/Ag+ Competition in Type I Copper Proteins (T1Cu)

et al. 2023

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Due to the similarity in the basic coordination behavior of their mono-charged cations, silver biochemistry is known to be linked to that of copper in biological systems. Still, Cu+/2+ is an essential micronutrient in many organisms, while no known biological process requires silver. In human cells, copper regulation and trafficking is strictly controlled by complex systems including many cytosolic copper chaperones, whereas some bacteria exploit the so-called “blue copper” proteins. Therefore, evaluating the controlling factors of the competition between these two metal cations is of enormous interest. By employing the tools of computational chemistry, we aim to delineate the extent to which Ag+ might be able to compete with the endogenous copper in its Type I (T1Cu) proteins, and where and if, alternatively, it is handled uniquely. The effect of the surrounding media (dielectric constant) and the type, number, and composition of amino acid residues are taken into account when modelling the reactions in the present study. The obtained results clearly indicate the susceptibility of the T1Cu proteins to a silver attack due to the favorable composition and geometry of the metal-binding centers, along with the similarity between the Ag+/Cu+-containing structures. Furthermore, by exploring intriguing questions of both metals’ coordination chemistry, an important background for understanding the metabolism and biotransformation of silver in organisms is provided.

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“…HAp has the ability to incorporate isomorphic substituents, such as magnesium (Mg), sodium (Na), strontium (Sr), silver (Ag), copper (Cu), etc., due to its flexible and stable crystalline structure [ 20 ]. The addition of antibacterial ions such as Ag [ 21 , 22 ], Cu [ 23 , 24 ], Zn [ 25 ], and Ga [ 26 ] provides antibacterial assets to CaPs. Tailoring a biomaterial with the aforementioned capacities could help to prevent bacterial growth at the surgical site after implantation.…”

Section: Introductionmentioning

confidence: 99%

Gallium-Doped Hydroxyapatite Shows Antibacterial Activity against Pseudomonas aeruginosa without Affecting Cell Metabolic Activity

Mosina

Siverino

Stipniece

et al. 2023

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Calcium phosphates (CaPs) have been used in bone regeneration for decades. Among the described CaPs, synthetic hydroxyapatite (HAp) has a chemical composition similar to that of natural bone. Gallium-containing compounds have been studied since the 1970s for the treatment of autoimmune diseases and have shown beneficial properties, such as antibacterial activity and inhibition of osteoclast activity. In this study, we synthesized hydroxyapatite (HAp) powder with Ga doping ratios up to 6.9 ± 0.5 wt% using the wet chemical precipitation method. The obtained products were characterized using XRD, BET, FTIR, and ICP-MS. Ga3+ ion release was determined in the cell culture media for up to 30 days. Antibacterial activity was assessed against five bacterial species: Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus pyogenes. The biocompatibility of the GaHAp samples was determined in human fibroblasts (hTERT-BJ1) through direct and indirect tests. The structure of the synthesized products was characteristic of HAp, as revealed with XRD and FTIR, although the addition of Ga caused a decrease in the crystallite size. Ga3+ was released from GaHAp paste in a steady manner, with approximately 40% being released within 21 days. GaHAp with the highest gallium contents, 5.5 ± 0.1 wt% and 6.9 ± 0.5 wt%, inhibited the growth of all five bacterial species, with the greatest activity being against Pseudomonas aeruginosa. Biocompatibility assays showed maintained cell viability (~80%) after seven days of indirect exposure to GaHAp. However, when GaHAp with Ga content above 3.3 ± 0.4 wt% was directly applied on the cells, a decrease in metabolic activity was observed on the seventh day. Overall, these results show that GaHAp with Ga content below 3.3 ± 0.4 wt% has attractive antimicrobial properties, without affecting the cell metabolic activity, creating a material that could be used for bone regeneration and prevention of infection.

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Gallium as an Antibacterial Agent: A DFT/SMD Study of the Ga³⁺/Fe³⁺ Competition for Binding Bacterial Siderophores

Cited by 42 publications

References 67 publications

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

Cu+/Ag+ Competition in Type I Copper Proteins (T1Cu)

Gallium-Doped Hydroxyapatite Shows Antibacterial Activity against Pseudomonas aeruginosa without Affecting Cell Metabolic Activity

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Gallium as an Antibacterial Agent: A DFT/SMD Study of the Ga3+/Fe3+ Competition for Binding Bacterial Siderophores

Cited by 42 publications

References 67 publications

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

Zinc and Its Critical Role in Retinitis pigmentosa: Insights from DFT/SMD Calculations

Cu+/Ag+ Competition in Type I Copper Proteins (T1Cu)

Gallium-Doped Hydroxyapatite Shows Antibacterial Activity against Pseudomonas aeruginosa without Affecting Cell Metabolic Activity

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Product

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Gallium as an Antibacterial Agent: A DFT/SMD Study of the Ga³⁺/Fe³⁺ Competition for Binding Bacterial Siderophores