The field of metal toxicology is vast, and although a wealth of information exists to account for bacterial resistance mechanisms towards metals, much less is known about the molecular and cellular targets of toxic metals in microorganisms.
Every metal atom has chemical properties that give rise to characteristic interactions with donor ligands, including reduction potential and metal speciation, both within cells and in the extracellular environment. These are key determinants of microbial toxicity.
Metal uptake is an important first step for poisoning. Bacterial uptake of non-essential metals occurs through routes normally reserved for essential organic and inorganic ions, and transporters from several families are now known to be involved.
Recent advances have begun to define the mechanisms of antimicrobial metal toxicity. These include the production of reactive oxygen species and free radicals, and the depletion of antioxidants; protein dysfunction and loss of enzyme activity; damage to cellular membranes and disruption of electron transport; interference with nutrient acquisition; and genotoxicity.
Our increased understanding of microbial metal toxicology is ushering in a new era for the rational design of metal-based antimicrobial agents. New innovations include antibacterial metal nanoparticles, abiotic metal surfaces and coatings, and the use of siderophores as delivery vehicles for toxic metals.
Metal-based antimicrobial therapies hold great promise as alternatives to antibiotics, but their potential for toxicity limits their applications. Care should be taken to protect human health and to minimize the damage that might occur to natural ecosystems as a result of the commercial use of metal-based antimicrobial technology.
Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, we describe the chemical and toxicological principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only our understanding of metal toxicity but also the design of metal-based compounds for use as antimicrobial agents and alternatives to antibiotics.
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J.A.L. is supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council (NSERC) of Canada. J.J.H. is supported by a fellowship from the Canadian Institute for Health Research (CIHR). Research in the laboratory of R.J.T. is supported by a Discovery Grant from the NSERC and an Operating Grant from the CIHR.
The authors declare no competing financial interests.
- Essential metals
Metals that are required for the normal physiology and function of organisms; these include Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Se and Mo. Thus far, Cd has been found to be essential for the function of only one enzyme in a few bacterial species
- Non-essential metals
Metals that have no known biological function for an organism.
Chemical compounds in which a heterocyclic ring has been formed through the coordinate bonding of a metal atom to at least two non-metal atoms.
Materials containing particles with an external dimension in the size range of 1–100 nm. At the nanoscale (10−9 m) range, materials can have novel mechanical, electromagnetic and chemical properties that distinguish them from the same material in bulk.
Chemical agents that are capable of destroying a living organism.
- Transition metals
Elements that either have an incomplete d sub-shell of electrons or can give rise to cations with an incomplete d sub-shell. These include all elements in groups 3–12 of the periodic table, with the exception of the lanthanides and actinides.
- Other metals
Any of the metallic elements within groups 13–15 of the periodic table.
Chemical elements with properties that resemble those of both metals and non-metals; these elements include B, Si, Ge, As, At, Te and Po.
- Hyperosmotic shock
A sudden increase in the solute concentration surrounding a cell, resulting in water leakage from the cell through osmosis. This activity disrupts normal transport and metabolic processes.
- Donor atom selectivity
The principle that, within a mixture of various ligands and metals, differences in affinity will result in the formation of specific types and quantities of coordination complexes.
The distinct chemical forms, compounds and concentrations in which an element occurs in its milieu.
- Coordination chemistry
The science concerned with the interactions of organic and inorganic ligands with a central metal atom.
- Ligand field theory
An application of molecular orbital theory that describes the bonding and orbital arrangements of transition metals in coordination complexes.
- Ionic mimicry
In the context of this Review, the ability of an unbound, cationic metal species to imitate an essential element or cationic form of that element.
- Molecular mimicry
In the context of this Review, the phenomenon whereby a complex formed between a metal species and a ligand serves as a structural or functional homologue of another endogenous biomolecule.
- Hard–soft acid base theory
An empirically derived chemical theory that helps us to understand the factors that drive reactions in complex mixtures of inorganic and organic reactants.
- Standard electrode potentials
The reduction potential of a half-reaction (in Volts) relative to the standard hydrogen electrode at precisely defined conditions (25 °C, 1 atm and a 1 M concentration for each aqueous species).
- Valence electrons
The electrons of an atom that participate in the formation of chemical bonds.
An anionic compound in which any element is bonded to O.
- Electron paramagnetic resonance
(EPR). A spectroscopic technique for studying materials with unpaired electrons.
- Reactive oxygen species
(ROS). Highly reactive, cytotoxic molecules formed by the incomplete, one-electron reduction of O. ROS include the superoxide anion (O2•−), peroxides (such as H2O2), the hydroxyl radical (OH•) and hypochlorite (HOCl).
- Metal-catalysed oxidation
A free radical-generating system in which a Fenton-active metal catalyses the oxidative modification of a biomolecule.
The thermodynamically favourable oxidation of a reduced compound by O2. Certain metals can behave as catalysts to increase the rate of this reaction.
- Free radical
Any atomic or molecular species that is capable of independent existence and contains one or more unpaired electrons. According to this definition, many transition metal ions are considered free radicals.
A tripeptide antioxidant (Glu-Cys-Gly) in which a γ-peptide bond joins the primary amine group of cysteine to the carboxyl group of the glutamate side chain. Equilibrium between reduced glutathione (GSH) and oxidized glutathione (GSSG) helps to maintain the cellular redox state of many bacterial species.
- Diffusion-controlled rate
A chemical reaction rate so rapid that it is restricted only by the diffusion rates of the reactants in solution.
- Lewis acid
An electron-pair acceptor that is able to react with a Lewis base to form an adduct by sharing an electron pair provided by the Lewis base.
- δ-aminolevulinic acid dehydratase
(ALAD). An evolutionarily conserved enzyme that catalyses the production of porphobilinogen, a key precursor in the haem biosynthesis pathway.
- Chemiosmotic potential
The motive force generated by a transmembrane Na+ or proton gradient.
- Thiobarturic acid-reactive substances
(TBARS). By-products of lipid peroxidation, such as malondialdehyde, that can react with thiobarbituric acid to produce fluorescent adducts. These adducts are used to indirectly detect and quantify fatty acid peroxidation.
- S-sparing response
A physiological adaptation in yeast that modifies the proteome by reducing the abundance of S-rich proteins.
- Ames test
A microbiological assay that is used to assess the mutagenic potential of chemical compounds.
Particulates of a substance that are evenly distributed (and thus known as the dispersed phase) throughout a dispersion medium (known as the continuous phase).
A microporous aluminosilicate mineral that can adsorb water and ions.
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Lemire, J., Harrison, J. & Turner, R. Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat Rev Microbiol 11, 371–384 (2013). https://doi.org/10.1038/nrmicro3028
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