Abstract
Due to the emergence of multi-drug resistant strains, development of novel antibiotics has become a critical issue. One promising approach is the use of transition metals, since they exhibit rapid and significant toxicity, at low concentrations, in prokaryotic cells. Nevertheless, one main drawback of transition metals is their toxicity in eukaryotic cells. Here, we show that the barriers to use them as therapeutic agents could be mitigated by combining them with silver. We demonstrate that synergism of combinatorial treatments (Silver/transition metals, including Zn, Co, Cd, Ni, and Cu) increases up to 8-fold their antimicrobial effect, when compared to their individual effects, against E. coli and B. subtilis. We find that most combinatorial treatments exhibit synergistic antimicrobial effects at low/non-toxic concentrations to human keratinocyte cells, blast and melanoma rat cell lines. Moreover, we show that silver/(Cu, Ni, and Zn) increase prokaryotic cell permeability at sub-inhibitory concentrations, demonstrating this to be a possible mechanism of the synergistic behavior. Together, these results suggest that these combinatorial treatments will play an important role in the future development of antimicrobial agents and treatments against infections. In specific, the cytotoxicity experiments show that the combinations have great potential in the treatment of topical infections.
Highlights
In the past three decades, global usage of antibiotics has become disproportionate, and, in the majority of instances, unsuitable[1]
We here hypothesize that treatments involving silver salts and transition metal combinations (STMCs) will exhibit synergistic antimicrobial effects, when compared to the effect of the individual compounds
To evaluate the properties of the different STMCs, we analyzed the synergistic effects of antimicrobial activity in E. coli (Gram-negative microorganism) and B. subtilis (Gram-positive microorganism)
Summary
In the past three decades, global usage of antibiotics has become disproportionate, and, in the majority of instances, unsuitable[1]. Hereafter, during the last decade, several health supplies, such as textile materials[17, 18], implants, catheters, and gauze pads[7, 8], have made extensive use of silver species and engineered delivery systems involving silver derivatives as antimicrobial agents[6, 7, 10, 16] These antimicrobial developments have been focused to combat multi-drug resistant bacteria[19]. ROS stress responses have been observed at lower concentrations when using CuO nanoparticles with an E. coli biosensor at 0.1 mM Cu30 It is a well-documented fact that one of the main limitations in using transition metals as therapeutic agents is their toxicity to eukaryotic cells. The cytotoxicity of transition metals has been reported in the literature for human gingival fibroblast (HGF)[31], TC50s of 78.7, 344, 705.8 and 872.9 μM, for Cd, Cu, Co, Ni respectively, and for HeLa cells[32] the TC50 of Zn has been reported to be 600 μM
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