Synergistic Antimicrobial Effects of Silver/Transition-metal Combinatorial Treatments

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.

A fast impedance-based antimicrobial susceptibility test

“…Optical flow cytometry has been widely utilised to monitor bacterial growth by a combination of cell size (determined from optical scatter) and fluorescent dyes (e.g. to measure viability) 16 – 18 . In comparison, impedance cytometry is a label-free method that directly measures both cell volume (size) and other phenotypic changes that are reflected in the electrical signature.…”

“…However, differentiation between antimicrobial exposed and unexposed populations has proved difficult and new approaches such as adaptive multi-dimensional statistics have been developed 17 . An assay for carbapenem resistance has been developed that uses acoustic-focusing flow cytometry to deliver a rapid S/R classification together with a quantitative MIC in ~2 h from a clinical isolate 18 , 19 . Flentie et al 20 introduced a novel assay that measured bacterial concentrations by binding a small-molecule amplifier to the bacterial surface.…”

Spontaneous mutation in the AgrRS two-component regulatory system ofCupriavidus metalliduransresults in enhanced silver resistance

“…1,4 Furthermore, the increase in occurrence and number of antibiotic-resistant strains contributed to the resurgence in the interest and use, including combating multi-drug resistant bacteria. 57,58 The potential of microorganisms to develop resistance to silver and AgNPs 59,60 and the incidence of silverresistant determinants in many environments, including those where the use of silver compounds was restricted, raises the concern for their widespread use and co-selection for antibiotic resistance. Together with the health and environmental risks associated with the increased use of nanotechnology, the European Commission advised that more data is needed to better understand the bacterial response to ionic silver and silver nanoparticles.…”

Handling (Nano)Silver as Antimicrobial Agent: Therapeutic Window, Dissolution Dynamics, Detection Methods and Molecular Interactions

“…The knowledge about the beneficial health effects of Ag dates back to ancient Egypt and Rome, Ayurvedic medicine in India, and traditional Chinese medicine . Silver coins have for instance been used to preserve drinking water or milk from microbial contamination .…”