A Silver Bullet?

When my sister went to get her ears pierced over the summer, my mother recounted how, instead of using devices like the sterilized piercing guns used today, Indian people used to use thin wires of silver to pierce their ears because of its supposed antimicrobial properties. This intrigued me. Of course I had heard of molecules like penicillin that could kill off bacteria, but never before had I considered that a single, naturally occurring element would be able to accomplish the same. How does this seemingly benign molecule cause so much damage?

The transition metal itself is biologically inert; the real structural damage stems from its Ag+ ion. This is released when Ag comes into contact with moisture (Kenyon University & Garduque), and does its work inside the microbe itself. I stopped as soon as I read that last part. Something didn’t seem right. I had learned from my AP Biology class that the majority of cell membranes are hydrophobic. They consist mainly of a phospholipid bilayer with the polar hydrophilic heads facing outwards into the environment and inwards towards the cell’s cytoplasm, and the long, non-polar hydrophobic tails made of hydrocarbons chains in-between. These tails don’t like to let polar atoms and molecules in and out by themselves, and I thought it highly unlikely that microbes would have special protein channels built to let in damaging substances. So how did these Ag+ molecules get in in the first place?

figure_04_14_labeled

Figure 1: The Phospholipid Bilayer

(Midlands Technical College, n.d.)

A while of digging later, I had no definitive answer. Some research hypothesized that the ions got through via protein channels made for other ions (Kenyon University & Garduque), but since there wasn’t any conclusive evidence I still remained somewhat skeptical. I continued to research the effects of the Ag+ ions, tough, and the evidence I found in favor of its microbial properties was strong enough for me to overlook this tiny blip.

What I found was that Ag+ works in three major ways: by reacting with the disulfide (R-S-S-R) and sulfhydryl (R-S-H) groups of microbial protein structures, by interacting with the microbial DNA, and by damaging the membrane structures of the cells. In the first method, the interactions of the ion change the quaternary (outer) structure of some of the microbes key proteins and enzyme, leaving it unable to function properly. The ion reacts to form, “a stable S-Ag” bond with the sulfhydryl-containing compounds, which are involved in, “trans-membrane energy generation and ion transport,” located in the microbial cell membrane, and are also believed to, “take part in catalytic oxidation reactions that result in the formation of disulfide bonds,” which are key components of a protein’s outer structure. The latter doesn’t involve Ag+ acting as reactant, but rather as a catalyst between existing the oxygen and hydrogen portions of the sulfhydryl groups. This reaction also ends up releasing H2O as a product (Jung, Koo, Kim, Shin, Kim & Park)

500px-Quaternary_structure

Figure 2:“Structure of the protein 1EFN, with focus on the quaternary structure.”

(Wikipedia, 2012)

Next, while it is clear that the Ag+ ions do have effects on microbial DNA, it is unclear exactly how it interacts with the DNA. Some scientists suggest that, “…they interact preferentially with bases in the DNA (Jung, Koo, Kim, Shin, Kim & Park),” while others think that the ions’ various other reactions in the cell, “…lead to an increased production of reactive oxygen species,” that in turn damages the microbe’s DNA, eventually leading to its death (Morones-Ramirez, Winkler, Spina & Collins, 2013). Finally, the microbe’s increased cell membrane permeability, which is also said to occur as a byproduct of these reactions and subsequent metabolic disruption and homeostatic iron levels, which, “…[restores] antibiotic susceptibility to a resistant bacterial strain (Morones-Ramirez, Winkler, Spina & Collins, 2013).”It is important to note, however, that this does not reverse the bacterial resistance, only temporarily weakens it.

400px-FIGURE_3_Feng_et_al

Figure 3: “Figure 3. Treatment of cells with Ag+ results in DNA condensation, cell wall damage, and silver granule formation. (A) E. coli and (B) S. aureus cells with and without Ag+ treatment were observed with transmission electron microscopy (Feng et al., 2000).”

(Kenyon University, n.d.)

As much as it would be great to regard the Ag+ ion as an end to all our troubles, it’s not without its side effects. Some people are allergic to silver (Elsner & Hipler, 2006), and those that aren’t are in danger of having the element accumulate in their bodies (Fung & Bowen, 1996). Long-term intake can lead to increased levels of skin silver and/or silver sulfide particle levels. Sunlight causes these particles to darken, leading to a skin discoloration known as argyria (Elsner & Hipler, 2006). Furthermore, silver is no different from traditional antibiotics in that it is simply ‘another chemical’ in action. As such, it is plausible that overuse of it may eventually lead to increased silver resistance in bacteria, and then we would simply end up in the same place we are now with the antibiotic resistance problem; at best we’ll just delay our troubles. Still, since there’s little doubt in the actual antimicrobial properties of silver, all of this doesn’t completely take it off the table. If it were possible to distribute the dosages in a way to avoid some of the adverse side effects, we could take advantage of the aforementioned delay. Time is arguably the most valuable resource for humans, and with all of the major medical advances taking place in the modern age, that extra time might be just what we need to come up with a true solution.

Works Cited

Elsner, P., & Hipler, U. -. (2006). Silver in health care: Antimicrobial effects and

safety in use. Biofunctional Textiles and the Skin, 33, 17-34. doi: 10.1159/000093928

Retrieved from

http://www.karger.com/Article/Abstract/93928

Fung, M. C., & Bowen, D. L. (1996). Silver products for medical indications: Risk-

benefit assessment. Clinical Toxicology, 34(1), 119-126. doi: 10.3109/15563659609020246

Retrieved from

http://informahealthcare.com/doi/abs/10.3109/15563659609020246

Jung, W., Koo, H., Kim, K., Shin, S., Kim, S., & Park, Y.

(2008). Antibacterial Activity and Mechanism of Action of the Silver Ion in Staphylococcus aureus and Escherichia coli. Applied Environmental Microbiology, 74(7), 2171-2178 doi:10.11.28/AEM.02001-07.

Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292600/

Kenyon University. , & Garduque, G. (n.d.). Silver as an antimicrobial agent.

Retrieved from http://microbewiki.kenyon.edu/index.php/Silver_as_an_Antimicrobial_Agent

Midlands Technical College. (Producer). The Phospholipid

Bilayer [Web Graphic]. Retrieved from http://classes.midlandstech.edu/carterp/courses/bio225/chap04/lecture5.htm

Morones-Ramirez, J. R., Winkler, J. A., Spina, C. S., & Collins,

J. J. (2013). Silver enhances antibiotic activity against gram-negative bacteria. Science Translational Medicine, 5(190), 198ra81. doi: 10.1126/scitranslmed.3006276

Retrieved from:

http://stm.sciencemag.org/content/5/190/190ra81

Wikipedia. (Producer). (2012, August 27). Protein structure with focus on the

quaternary structure [Web Graphic]. Retrieved from http://en.wikipedia.org/wiki/File:Quaternary_structure.png

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