Metals to combat antimicrobial resistance

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.

Fig. 1. Chemical structures of metallophores and metallophore–antibiotic conjugates.

a, Examples of naturally occurring metallophores with different metal-binding motifs: enterobactin, an example of a catechol-based metallophore; ferrioxamine B, an example of a hydroxamate-based metallophore and staphyloferrin A, an example of an α-hydroxy carboxylate. b, Chemical structures of metallophore–antibiotic conjugates: albomycin δ1, a naturally occurring metallophore–antibiotic; cefiderocol, one of the first synthetic metallophore–antibiotics approved for clinical use; GSK3342830, BAL30072, MC-1 and MB-1, which are synthetic metallophore–antibiotics in clinical development from various pharmaceutical companies, as well as galbofloxacin and Ent-Cipro, which are synthetic metallophore–antibiotics prepared by academic groups. The metallophore in each example is shown in blue.

Fig. 2. Trojan horse strategy.

The metallophore–antibiotic conjugate sequesters iron from its local environment and is actively transported into the bacterial cell where the antibiotic portion of the compound can act on its target.

Fig. 3. Diversity in metals and structures accessible to metal complexes that have antibacterial activity.

The compounds shown contain chromium, manganese, iron, cobalt, copper, zinc, gallium, ruthenium, rhodium, palladium, silver, tungsten, rhenium, osmium, iridium, platinum or gold.

Fig. 4. Overview of the mechanisms of action of known antibiotics and metalloantibiotics.

Antibiotics can act by a number of different mechanisms. Unfortunately, there are relatively few metalloantibiotics for which the mechanism of action has been studied in detail. Illustrated here are the targets of compounds Re1, Re2, Ru1, Ru2 and auranofin. DHPS, dihydropteroate synthase; DHFR, dihydrofolate reductase; TrxR, thioredoxin reductase; mRNA, messenger RNA.

Fig. 5. Mechanism of action of antimicrobial photodynamic therapy.

A metal photosensitizer (PS) is activated from its ground state to a singlet excited state upon light irradiation. Through intersystem crossing (ISC), an excited triplet state is reached, which can transfer either an electron to surrounding biological substrates (type 1 mechanism) or energy to surrounding oxygen (type 2 mechanism), generating a suite of reactive species that can kill nearby bacteria. Energy can also be dissipated through internal conversion (IC), fluorescence or phosphorescence. M, metal; ROS, reactive oxygen species; S or ¹, singlet state; T or ³, triplet state; hν, photon energy, where h is Planck’s constant and ν is the frequency of light.

Fig. 6. Example structures of heterocyclic macrocycle metal photosensitizers.

The macrocyclic compounds, which are generally highly positively charged, can contain various different metals such as iron, lutetium, palladium, zinc or aluminium. Ac, acetate.

Fig. 7. Structures of metal photosensitizers reported to have antibacterial activity.

Various metals and ligand assemblies have the potential to be used as antibacterial photodynamic therapy agents. In general, aromatic conjugated ligands are used to fine-tune the photophysical properties of the resulting metal complex. Examples containing the metals ruthenium (PS-Ru1, ref. ; PS-Ru2, ref. ), iridium (PS-Ir1, ref. ), platinum (PS-Pt1, refs. ^,), copper (PS-Cu1, ref. ) and rhenium (PS-Re1, ref. ) have been reported. PS, photosensitizer; Ph, phenyl.

Fig. 8. Metal complexes for imaging bacterial infections.

A, Structures of imaging agents. B, The structure of [⁶⁸Ga]-PVD-PAO1 (Ba) and static PET–CT imaging of [⁶⁸Ga]-PVD-PAO1 (Bb and Bc) compared with [⁶⁸Ga]-citrate (Bd) and [¹⁸F]-FDG (Be) in a mouse muscle-infection model 45 min post-injection of Pseudomonas aeruginosa in one thigh and Escherichia coli or sterile inflammation in the other thigh. C, The structure of [⁶⁸Ga]-DFO-B (Ca) and static PET–CT imaging of [⁶⁸Ga]-DFO-B in a mouse thigh-infection model 45 min post-injection with P. aeruginosa (Cb) or Staphylococcus aureus (Cc) (yellow arrows indicate site of infection). PET, positron-emission tomography; CT, computed tomography; PAI, P. aeruginosa infection; ECI, E. coli infection; SI, sterile inflammation; TAFC, triacetylfusarinine; FOXE, ferrioxamine E; PVD, pyoverdine; FDG, fluorodeoxyglucose; DFO-B, desferrioxamine-B; ID g⁻¹, injected dose per gram of tissue; kBq ml⁻¹, kilobecquerel per millilitre. Part B reprinted from ref. , under a Creative Commons licence CC-BY 4.0. Part C reprinted from ref. , under a Creative Commons licence CC-BY 4.0.