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  • Review Article
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Metals to combat antimicrobial resistance

Nature Reviews Chemistry volume 7, pages 202–224 (2023)Cite this article

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Abstract

Bacteria, similar to most organisms, have a love–hate relationship with metals: a specific metal may be essential for survival yet toxic in certain forms and concentrations. Metal ions have a long history of antimicrobial activity and have received increasing attention in recent years owing to the rise of antimicrobial resistance. The search for antibacterial agents now encompasses metal ions, nanoparticles and metal complexes with antimicrobial activity (‘metalloantibiotics’). Although yet to be advanced to the clinic, metalloantibiotics are a vast and underexplored group of compounds that could lead to a much-needed new class of antibiotics. This Review summarizes recent developments in this growing field, focusing on advances in the development of metalloantibiotics, in particular, those for which the mechanism of action has been investigated. We also provide an overview of alternative uses of metal complexes to combat bacterial infections, including antimicrobial photodynamic therapy and radionuclide diagnosis of bacterial infections.

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Fig. 1: Chemical structures of metallophores and metallophore–antibiotic conjugates.
Fig. 2: Trojan horse strategy.
Fig. 3: Diversity in metals and structures accessible to metal complexes that have antibacterial activity.
Fig. 4: Overview of the mechanisms of action of known antibiotics and metalloantibiotics.
Fig. 5: Mechanism of action of antimicrobial photodynamic therapy.
Fig. 6: Example structures of heterocyclic macrocycle metal photosensitizers.
Fig. 7: Structures of metal photosensitizers reported to have antibacterial activity.
Fig. 8: Metal complexes for imaging bacterial infections.

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Acknowledgements

The CO-ADD screening described in this Review, which led to our focus on metalloantibiotics, was supported by the Wellcome Trust (UK; Strategic Funding Award: 104797/Z/14/Z) and The University of Queensland (Australia; Strategic Funding), which included salary support for M.A.T.B., A.G.E. and J.Z. A.F. thanks the SNSF for an Early Postdoc Mobility Fellowship (P2ZHP2_177997) that supported his work at The University of Queensland. A.D.V. is currently supported by an Australian National Health and Medical Research Council Ideas Grant (2004367), and A.G.E. and J.Z. are supported by the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (04CARB-X-X064).

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Authors and Affiliations

  1. Community for Open Antimicrobial Drug Discovery, Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia

    Angelo Frei, Anthony D. Verderosa, Alysha G. Elliott, Johannes Zuegg & Mark A. T. Blaskovich

  2. Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland

    Angelo Frei

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Contributions

M.A.T.B. proposed the initial structure of the Review, with contributions from all authors. A.F. drafted the introduction, ‘Metalloantibiotics’ and ‘Photoactivated metal complexes’ sections, with J.Z. contributing to the ‘Photoactivated metal complexes’ section. M.A.T.B. drafted the ‘Metals and bacteria’, ‘Zinc ionophores’ and ‘Metal complexes for imaging infections’ sections. A.D.V. drafted the description of the strategies based on uptake (‘Metallophores’). A.G.E. contributed to the section ‘Metals and bacteria’. All authors edited the final manuscript.

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Correspondence to Angelo Frei or Mark A. T. Blaskovich.

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Nature Reviews Chemistry thanks Raymond Turner, Grażyna Stochel, Sajjad Hussain Sumrra and Agnieszka Kyzioł for their contribution to the peer review of this work.

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Glossary

Antimicrobial resistance

This arises when microorganisms are able to either intrinsically resist, or evolve to resist, the effects of antimicrobial agents.

Inorganic compounds

Despite the lack of an agreed-upon definition in the literature, this is probably most accurately defined as ‘any compounds that are not organic’.

Ionophore

A molecule that increases the permeability of lipid membranes to specific ions.

Metalloantibiotic

A metal complex with antimicrobial properties.

Metallophore or siderophore

Low-molecular-mass organic ligands that are produced by microorganisms such as bacteria and fungi, to supply metal-ion nutrients to the organism.

Metal complex

Metal complexes or coordination complexes consist of one (or multiple) central metal atoms or ions and surrounding bound molecules or ions referred to as ligands.

Minimum inhibitory concentration

The lowest concentration of a compound required to inhibit visible growth of a microorganism, following overnight incubation in the presence of the microorganism.

Organometallic compounds

Although officially defined as any compounds containing a covalent carbon–metal bond, this description is often mistakenly generalized to all metal complexes that have organic ligands.

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Frei, A., Verderosa, A.D., Elliott, A.G. et al. Metals to combat antimicrobial resistance. Nat Rev Chem 7, 202–224 (2023). https://doi.org/10.1038/s41570-023-00463-4

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