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Silver ion-based antimicrobials: mechanisms of toxicity and resistance


Project Description

"The emergence and persistence of bacterial strains with resistance to multiple classes of antibiotics has led to renewed interest in the antimicrobial properties of silver ions. There has been a surge in the number of products on the market, both clinical and domestic, that contain antimicrobial silver compounds or nanoparticles, including topical burn creams, wound dressings, coatings on medical devices (e.g. catheters and stents), anti-odour fabrics, deodorants, washing machine filters, and laptop coatings. The development of improved antimicrobial silver coatings and silver nanoparticles continues to receive significant research funding worldwide.

Biologically relevant compounds containing thiol groups (R-SH), such as reduced glutathione (GSH), react with and thereby inactivate silver ions in a 1:1 molar ratio. When the thiol concentration of the culture medium is equivalent, the minimum inhibitory concentration (MIC) of silver ions to human cells is very similar to that for clinically relevant bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus and Eschericia coli (1). This suggests that the primary targets of silver are the same in human cells and bacteria, but the exact mechanism of silver toxicity is still unclear. Some evidence suggests that silver ions are toxic because they inactivate enzymes with metal-ion cofactors (2), most likely those involved in essential metabolic pathways that are common to prokaryotes and eukaryotes.

Given the increasing use of silver antimicrobials in a diverse range of clinical and domestic applications, it is vital to understand how microbes evolve resistance to silver ions and the prevalence of silver resistance genes in microbial communities. Currently the only reported mechanism of bacterial silver resistance involves a silver ion efflux pump, encoded by the sil operon, which is thought to actively remove silver ions from the cell (3). A recent study of silver resistance in clinical isolates suggests that the use of silver in wound management may be driving the spread of sil resistance genes via horizontal gene transfer of resistance plasmids (4). It is therefore important to understand how silver resistance evolves and to fully dissect the molecular mechanisms to limit the spread of resistance.

This research will investigate the molecular basis of silver ion toxicity to human pathogens (e.g. Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans) and human cells (e.g. dermal fibroblasts) in vitro. A range of molecular techniques (e.g. enzyme assays, live/dead stains, FACS, ROS assays, qRT-PCR, RNAseq) will be used to monitor toxic effects of Ag+, and ICP-OES / MS will be used to quantify metal ions in different cellular compartments under different silver regimes (e.g. silver nitrate, silver sulfadiazine, silver wound dressings, silver nanoparticles) and electron microscopy used to visualise damage to cell structures. Silver resistant microbes will be isolated from diverse samples (environmental and clinical) and the molecular basis of Ag+ resistance will be determined using whole genome sequencing, transcriptomics and cloning techniques (e.g. directed mutagenesis, expression of recombinant proteins).

Funding Notes

Eligibility:

Applicants should have a bachelors (at least 2.1 or equivalent) or master’s degree in a biological subject (e.g. Biology, Biochemistry, Microbiology, Genetics, Biomedicine, Biological Chemistry, Molecular Biology). Practical experience working in a microbiolgy or molecular biology laboratory is highly desired but not essential.

References

References:
1. Mulley, G. et al. (2014) Inactivation of the Antibacterial and Cytotoxic Properties of Silver Ions by Biologically Relevant Compounds. PLoS One 9, e94409
2. Xu, F.F. and Imlay, J.A. (2012) Silver(I), Mercury(II), Cadmium(II), and Zinc(II) Target Exposed Enzymic Iron-Sulfur Clusters when They Toxify Escherichia coli. Applied and Environmental Microbiology. 78(10):3614-21
3. Randall, C., Gupta, A., Jackson, N., Busse, D., O'neill, A. (2017) Silver resistance in Gram-negative bacteria: a dissection of endogenous and exogenous mechanisms. Journal of Antimicrobial Chemotherapy 70, 1037–1046
4. Finley P., Norton, R., Austin, C., Mitchell, A., Zank, S. et. al. (2015) Unprecedented Silver Resistance in Clinically Isolated Enterobacteriaceae: Major Implications for Burn and Wound Management. Antimicrobial Agents and Chemotherapy 59(8) pp: 4734-41"

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