Science suggests that Antimicrobial Copper kills bacteria with a rapid multifaceted attack.
The mechanisms by which solid copper damages and destroys bacteria and viruses is still being studied but sufficient work has been done to confirm the broad spectrum efficacy of the metal and its alloys such as brass and bronze. Importantly, even under the dry-touch conditions of a typical indoor environment, copper is able to permanently inactivate pathogens. By interacting with the cell structure, copper initiates a series of cascading events, including rapidly interrupting normal functions and compromising cell membrane integrity. This allows copper to enter the microbe structure and totally overwhelm the metabolism. The final stage is the breaking down of genomic material. As a whole, these numerous and complex reactions mean that resistance to copper alloys is extremely unlikely to be developed.
Mechanism of Action of Antimicrobial Copper
Many researchers have studied the mechanism of action related to the contact killing of bacteria when placed on copper alloy surfaces. In order to illustrate the variety of theories and the complexity of copper contact killing mechanism, the following previously published list1 of examples of modes of action proposed by various researches is reproduced below:
- The 3-dimensional structure can be altered by copper so that the proteins can no longer perform their normal functions. The result is inactivation of bacteria or viruses2.
- Copper complexes form radicals that inactivate viruses3,4.
- Copper may disrupt enzyme structures, and functions by binding to sulphur- or carboxylate-containing groups and amino groups of proteins5.
- Copper may interfere with other essential element take-up, such as zinc and iron.
- Copper facilitates deleterious activity in superoxide radicals. Repeated redox reactions on site-specific macromolecules generate OH- radicals, thereby causing 'multiple hit damage' at target sites6,7.
- Copper can interact with lipids, causing their peroxidation and opening holes in the cell membranes, thereby compromising the integrity of cells8. This can cause leakage of essential solutes, which in turn, can have a desiccating effect.
- Copper damages the respiratory chain in Escherichia coli cells9 and is associated with impaired cellular metabolism10.
- Faster corrosion correlates with faster inactivation of microorganisms. This may be due to increased availability of cupric ion, Cu2+, which is believed to be responsible for the antimicrobial action11.
- In inactivation experiments on the flu strain, H1N1, which is nearly identical to the H5N1 avian strain and the 2009 H1N1 (swine flu) strain, researchers hypothesized that copper’s antimicrobial action probably attacks the overall structure of the virus and therefore has a broad-spectrum effect12.
- Microbes require copper-containing enzymes to drive certain vital chemical reactions. Excess copper, however, can affect proteins and enzymes in microbes, thereby inhibiting their activities. Researchers believe that excess copper has the potential to disrupt cell function both inside cells and in the interstitial spaces between cells, probably acting on the cells’ outer envelope13.
In addition, a review article14, focusing on copper’s mode of action in bacteria presents an overview of these mechanisms.
However no single mechanism is broadly accepted. The possibilities are complex and multi-faceted. Clearly, studies of these mechanisms should be viewed as ongoing works in progress and to propose a specific mechanism is premature. Copper killing mechanisms need additional investigation and are expected to show different and complex interactions in different organism types.
Let us look at a bacterial cell and explore how copper could act on it.
I) Copper acts on the cell membrane:
In addition to a number of types of capsules or walls that lie outside the cell itself, bacterial cells have a cell membrane composed of a lipid matrix embedded with proteins. The role of the cell membrane is to provide a crucially important barrier between the cell’s interior and its environment and regulate what enters and leaves the cell. Large numbers and types of proteins are exposed at the outer or inner surface of the membrane and some penetrate across the membrane and are exposed on both surfaces. Maintenance of this complex structure and its proteins is essential for the life of the cell.
It is suggested that the production of oxidative species14,15, via a Fenton type reaction16, causes a loss in cell membrane integrity14,16. Extensive membrane damage is observed within minutes17 and cells removed from copper surfaces show a loss of cell integrity17. This loss in integrity, in turn, is expected to disrupt energy production via respiration (in bacteria the respiratory enzymes are cell membrane proteins), as well as a loss in control of the movement of water, ions – for example of hydrogen, sodium and potassium – as well as nutrients like sugar and amino acids. In addition, this damage to membrane integrity causes distortions in the membrane that potentially stimulate stress signals resulting in the activation of enzymes inside the cell that then degrade intracellular molecules including DNA, RNA and perhaps proteins. Finally, complete and extensive disruption of membrane structure could result in bursting of the cell membrane and the release of cellular contents.
II) Copper also enters the cell:
Cells have multiple mechanisms to protect against harmful intracellular levels of copper. These include pumping copper out of the cell (efflux) and combining it harmlessly (sequestering it) in protein complexes. Most of these mechanisms require energy, which may not be available in a cell with a compromised membrane. In addition, “inappropriate” binding of copper to specific proteins (enzymes) could lead to structural changes, loss-of-function, and/or stimulation of protein destruction. When a lethal dose level is reached, copper seems to interfere with normal cell functions, such as cell metabolism, and causes irreversible and complete destruction to the extent that the cells are non-viable18,19.
It is suggested that the primary effects of exposure to copper alloy surfaces are those that occur at the cell membrane20 and that DNA disintegration is a secondary effect15,16,21,22. As evidence that DNA degradation is secondary, researchers16 demonstrated that, in a 60% Cu alloy, no survivors were found after 45 minutes of exposure, but the genomic DNA was intact. The viewpoint that DNA degradation is a secondary effect, is not universally accepted23,24. Ultimately, this discrepancy, which may vary by organism and the copper content of the alloy it is placed upon, will only be resolved by additional research data.
However, all agree that copper kills bacteria and that all of the above cascading events lead to rapid and irreversible cell death in bacteria.
The terms 'copper resistant' and 'copper sensitive' are used to describe mutant strains exhibiting altered ability to grow in aqueous solutions of different concentrations of copper. One important question is whether the mechanism of resistance to dissolved copper in aqueous solutions is relevant to the copper killing seen on dry surfaces. In an investigation of copper-resistance and copper-sensitive mutant stains of E.coli 21, it was found that the sensitive strain lacking a specific copper detoxification system showed only a slight increase in sensitivity when exposed to two copper alloys surfaces containing either 60% or 65% copper. In contrast, the copper-resistant strain, which expresses enhanced levels of the copper detoxification system, shows no improvement in survival on these copper alloy surfaces and, in fact, may be slightly more sensitive21. These findings strongly suggest that copper resistance and the copper detoxification systems play a minor role, if any, in the ability of dry copper alloy surfaces to kill bacteria21. To be more specific, the term 'copper resistance' is not applicable to the killing observed on dry copper alloy surfaces.
It is important to note that copper is an essential nutrient and required for several metabolic functions, but is toxic when internal copper levels become excessive. Thus, cells must tightly regulate internal copper levels and have evolved several mechanisms for doing this. Copper resistant strains have enhanced these mechanisms and are better able to cope with higher levels of copper within the cell. In contrast, antibiotics play no role in bacterial metabolism or reproduction. Normal bacteria are highly sensitive to even low levels of these metabolic poisons. Antibiotic resistant strains are able to bypass the toxic effect of antibiotics and reproduce even in the presence of the antibiotic. Thus, copper resistance and antibiotic resistance are not comparable.
Copper, however, may have a role in combatting the evolution of antibiotic-resistant bacteria by continuously reducing the environmental reservoirs of microbes which otherwise act as breeding grounds for mutant forms.
Viruses are referred to as obligate parasites. Thus, they cannot complete their life cycle without exploiting a suitable host. They consist of a set of reproduction instructions (DNA or RNA) encased in a capsule (capsid) that is capable of gaining entry into the host cell. The host cells’ metabolic systems are then used for producing more viruses. However, copper alloys can permanently and irreversibly inactivate viruses and thus may have the potential to significantly decrease their pathobiological consequences, probably by disrupting their ability to invade host cells. The data suggests25 that, in murine norovirus, an RNA virus, that capsid integrity is compromised upon contact with copper resulting in irreversible and permanent inactivation of the viral particles. In a subsequent study26, a strain of human coronavirus, also an RNA virus, was shown to be inactivated by copper alloy contact. Taken together, these studies suggest that copper alloy surfaces might exhibit antiviral activity against other important RNA viruses for which transmission via touch surfaces is important, including virulent respiratory viruses and Ebola virus. Other types of viruses, including DNA viruses, could also be sensitive to copper alloy surface exposure and continued investigations in this area are essential.
Copper and copper alloys are engineering materials that are durable, colourful and recyclable and are widely available in various product forms suitable for a range of manufacturing purposes. Copper and its alloys offer a suite of materials for designers of functional, sustainable and cost-effective products.
Copper and certain copper alloys have intrinsic antimicrobial properties (so-called ‘Antimicrobial Copper’) and products made from these materials have an additional, secondary benefit of contributing to hygienic design. Products made from Antimicrobial Copper are a supplement to, not a substitute for standard infection control practices. It is essential that current hygiene practices are continued, including those related to the cleaning and disinfection of environmental surfaces.
- Antimicrobial properties of copper on Wikipedia.
- The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses. Thurman RB, Gerba CP (1989). CRC Critical Reviews in Environmental Control 18(4): 295–315.
- Photosensitive DNA cleavage and phage inactivation by copper(II)-camptothecin. Kuwahara, J, Suzuki, T., Funakoshi, K, Sugiura, Y (1986). Biochemistry 25 (6): 1216–1221.
- Inhibition of avian myeloblastosis virus reverse transcriptase and virus inactivation by metal complexes of isonicotinic acid hydrazide. Vasudevachari, M, Antony, A (1982). Antiviral Research 2 (5): 291–300.
- Interactions of heavy metals with bacteria. Sterritt, R, Lester, J (1980). The Science of the total environment 14 (1): 5–17.
- On the cytotoxicity of vitamin C and metal ions. A site-specific Fenton mechanism. Samuni, A, Aronovitch, J, Godinger, D, Chevion, M, Czapski, G (1983). European Journal of Biochemistry / FEBS 137 (1–2): 119–124.
- Roles of Copper and Superoxide Anion Radicals in the Radiation-Induced Inactivation of T7 Bacteriophage. Samuni, A, Chevion, M, Czapski, G (1984). Radiat. Res. 99 (3): 562–572.
- Copper-induced formation of reactive oxygen species causes cell death and disruption of calcium homeostasis in trout hepatocytes. Manzl, C Enrich, J, Ebner, H, Dallinger, R, Krumschnabel, G (2004). Toxicology 196 (1–2): 57–64.
- Evidence for the role of copper in the injury process of coliform bacteria in drinking water. Domek, M., Lechevallier, M., Cameron, S., McFeters, G. (1984). Applied and environmental microbiology 48 (2): 289–293.
- Metabolism of Escherichia coli injured by copper. Domek, M, Robbins, J, Anderson, M, McFeters, G (1987). Canadian journal of microbiology 33 (1): 57–62.
- Copper Alloys for Human Infectious Disease Control. Michels, H, Wilks, S, Noyce, J, Keevil, CW (2005). Presented at the Materials Science and Technology Conference, September 25–28, 2005, Pittsburgh, PA; Copper for the 21st Century Symposium.
- Anti-Microbial Characteristics of Copper. Michels, H (October 2006), ASTM Standardization News 34 (10): 28–31, retrieved 2014-02-03.
- Lowering Infection Rates in Hospitals and Healthcare Facilities – The Role of Copper Alloys in Battling Infectious Organisms. BioHealth Partnership Publication (2007): Edition 1, March.
- Physicochemical properties of copper important for its antimicrobial activity and development of a unified model. Hans, M, Mathews, S, Mucklich, F, Solioz, M. (2016). Biointerphase 11 (1): 018902 1-8 (published on line November 16, 2015).
- Antimicrobial copper alloy surfaces are effective against vegetative but not sporulated cells of gram-positive Bacillus subtilis. San, K, Long, J, Michels, C, Gadura, N (2015). MicrobiologyOpen, 4 (5) 753-763.
- Membrane Lipid Peroxidation in Copper Alloy-Mediated Contact Killing of Escherichia coli. Hong, R, Kang, T. Michels, C. Gadrura, N (2012). Applied and Environmental Microbiology 78 (60): 1776-1784.
- Bacterial Killing by Dry Copper Surfaces. Espırito Santo, C, Lam, E, Elowsky, C, Quaranta, D, Domaill, D, Grass, G (2011). Applied and Environmental Microbiology, 77, 794-802.
- Mechanism of copper surface toxicity in Escherichia coli O157: H7 and Salmonella involves immediate membrane depolarization followed by slower rate of DNA destruction which differs from that observed for Gram-positive bacteria. Warnes, S, Caves, V, & Keevil, CW (2012). Environmental Microbiology, 14, 1730–1743.
- Potential action of copper surfaces on meticillin-resistant Staphylococcus aureus. Weaver, L, Noyce, J, Michels, H, & Keevil, CW (2010). Journal of Applied Microbiology, 109, 2200–2205.
- Metallic Copper as an Antimicrobial Surface. Applied and Environmental Microbiology. Grass, G, Rensing, C, Solioz, M (2011). 77, 1541-1547.
- Contribution of copper ion resistance to survival of Escherichia coli on metallic copper surfaces. Espırito Santo, C, Taudte, N, Nies, D, & Grass, G (2008). Applied and Environmental Microbiology, 74, 977–986.
- Metallic Copper as an Antimicrobial Surface. Grass, G, Rensing, C, Solioz, M (2011). Journal of Applied Microbiology, 77, 1541-1547.
- Biocidal Efficacy of Copper Alloys against Pathogenic Enterococci Involves Degradation of Genomic and Plasmid DNAs. Warnes, S, Green, S, Michels, H, Keevil, CW (2010). Applied and Environmental Microbiology, 76, 5390-5401.
- Mechanism of Copper Surface Toxicity in Vancomycin-Resistant Enterococci following Wet or Dry Surface Contact. Warnes, S, Keevil, CW (2011). Applied and Environmental Microbiology, 77, 6049-6059.
- Inactivation of Murine Norovirus on a Range of Copper Alloy Surfaces Is Accompanied by Loss of Capsid Integrity. Warnes, S, Summersgill, E, Keevil, CW (2015). Applied and Environmental Microbiology, 81, 1085-1091.
- Human Coronavirus 229E Remains Infectious on Common Touch. Warnes, S, Little, Z, Keevil, CW (2015). mbio.asm.org, 6, 1-10.