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Copper, An Ancient Remedy Returning to Fight Microbial, Fungal and Viral Infections

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Copper has potent biocidal properties. Copper ions, either alone or in copper complexes, have been used for centuries to disinfect liquids, solids and human tissue. This manuscript reviews the biocidal mechanisms of copper and the current usages of copper and copper compounds as antibacterial, antifungal and antiviral agents, with emphasis on novel health related applications. These applications include the reduction of transmission of health-associated (nosocomial) pathogens, foodborne diseases, and dust mites loads and treatment of fungal foot infections and wounds. Possible future applications include filtration devices capable of deactivating viruses in solutions, such as contaminated blood products and breastmilk.
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272 Current Chemical Biology, 2009, 3, 272-278
1872-3136/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.
Copper, An Ancient Remedy Returning to Fight Microbial, Fungal and
Viral Infections
Gadi Borkow
*
and Jeffrey Gabbay
Cupron Scientific, Ligad Center 2, First Floor, Rechov HaMa'ayan 4, Modiin 71700, Israel
Abstract: Copper has potent biocidal properties. Copper ions, either alone or in copper complexes, have been used for
centuries to disinfect liquids, solids and human tissue. This manuscript reviews the biocidal mechanisms of copper and the
current usages of copper and copper compounds as antibacterial, antifungal and antiviral agents, with emphasis on novel
health related applications. These applications include the reduction of transmission of health-associated (nosocomial)
pathogens, foodborne diseases, and dust mites loads and treatment of fungal foot infections and wounds. Possible future
applications include filtration devices capable of deactivating viruses in solutions, such as contaminated blood products
and breastmilk.
Keywords: Copper, biocide, fungicide, antiviral, acaricidal, nosocomial infections, wound healing.
INTRODUCTION
Copper has been used as a biocide for centuries [1]. In
ancient Egypt (2000 BC), copper was used to sterilize water
and wounds. The ancient Greeks in the time of Hippocrates
(400 BC) prescribed copper for pulmonary diseases and for
purifying drinking water. Gangajal, “Holy water”, given to
Hindu devotees to drink as a blessed offering, is stored in
copper utensils as it keeps the water sparkling clean. During
the Roman Empire, copper cooking utensils were used to
prevent the spread of disease. The early Phoenicians nailed
copper strips to ships’ hulls to inhibit fouling and thus in-
crease speed and maneuverability. The Aztecs used copper
oxide and malachite for treating skin conditions. Early
American pioneers moving west across the American conti-
nent put copper coins in large wooden water casks to provide
safe drinking water for their long journey. By the 18th cen-
tury, copper had come into wide clinical use in the Western
world in the treatment of lung and mental disorders. In the
Second World War, Japanese soldiers put pieces of copper in
their water bottles to help prevent dysentery. Copper sul-
phate was (and is still) highly prized by some inhabitants of
Africa and Asia for healing sores and skin diseases.
Were all these civilizations right in using copper for the
above mentioned purposes? Indeed they were! The following
sections review scientific studies demonstrating the potent
biocidal properties of copper and copper compounds and
their current uses in health related applications.
COPPER BIOCIDAL ACTIVITIES
The wide use of copper due to its antifungal properties
started in 1761, when it was discovered that seed grains
soaked in copper sulphate inhibited seed-borne fungi. Within
a few decades, the practice of treating seed grains with cop-
per sulphate had become so general and effective that today
seed-borne fungi are no longer of any economic importance.
*Address correspondence to this author at the Cupron Scientific, Ligad
Center 2, First Floor, Rechov HaMa'ayan 4, Modiin 71700, Israel;
E-mail: gadi@cupron.com
In the 1880s a mixture of copper sulphate, lime and water
(called “Bordeaux mixture") and a mixture of copper sul-
phate and sodium carbonate (called “Burgundy mixture”)
became the fungicide of choice in the U.S. and France, re-
spectively, for spraying grapes and vines to fight mildew.
The fungicidal properties of copper were demonstrated in
controlled laboratory studies starting in the early 1950s (e.g.
[2-4]) and since then copper and copper compounds have
been shown to effectively kill a wide range of yeast and
fungi such as Aspergillus carbonarius [5]; Aspergillus fumi-
gatus [6]; Aspergillus niger [6-8]; Aspergillus oryzae [7];
Candida albicans [6,8-13]; Cryptococcus neoformans [6];
Epidermophyton floccosum [6]; Microsporum canis [6]; My-
rothecium verrucaria [7]; Saccharomyces cerevisiae [14,15];
Torulopsis pintolopesii [9]; Trichoderma viride [7]; Tricho-
phyton mentagrophytes [7,8,13] and Tricophyton rubrum
[6,13]. Thus, copper fungicides have become indispensable
and many thousands of tons are used annually all over the
world in agriculture [16,17]. For example, copper sulphate
and copper hydroxide are employed for the control of downy
mildew on grapes and green slime in farm ponds, rice fields,
irrigation and drainage canals, rivers, lakes and swimming
pools [17]. However, copper compounds may be very toxic
to fish and other organisms. The environmental hazards re-
sulting from copper build-up in sediments and the need for
high dosages have led to a constant search for and produc-
tion of compounds that provide the copper in a chelated form
(e.g. [18-20]). Chelated copper is non-reactive with other
chemical constituents in the water. For example, the copper
water-insoluble compound, copper-8-quinolinolate and some
of its derivates [7] are used in fruit-handling equipment. This
compound is also used to reduce environmental contamina-
tion of fungi in hospitals at concentrations above 0.4 g/ml
[16], since infection with fungi, such as Aspergillus spp, is a
major problem among immunocompromised patients, such
as AIDS patients.
Copper sulphate has been in use since 1838 for preserv-
ing timber and is today the base for many proprietary wood
preservatives [21]. Copper is also used as the active ingredi-
ent in products that prevent roof moss formation, such as
Copper Fighting Microbial, Fungal and Viral Infections Current Chemical Biology, 2009, Vol. 3, No. 3 273
copper granules found in 3M Scotchgard™ Algae Resistant
Roofing System [22]. Interestingly, the growth of barnacles,
seaweed, tubeworms, and other organisms on boat bottoms
produces surface roughness that increases turbulent flow,
acoustic noise, drag, and fuel consumption. An average in-
crease of 10 m in hull roughness can result in a 1% increase
in fuel consumption! This has led to the painting of boat bot-
toms with copper-containing paints that reduce fouling and
microbial biofilm formation in ships and save energy [23],
and now copper is quite commonly used in antifouling paints
[23-25].
Several copper compounds, such as copper sulphate,
copper nitrate and cupric chloride-bis-n-dodecylamine, are
potent molluscicides. For example, the following snails have
been shown to be killed by these compounds: Biomphalaria
glabrata [26]; Biomphalaria alexandrina [27-29] and Lym-
naea natalenesis [28,29]. Control of snails may be an impor-
tant strategy in fighting some human diseases, such as bil-
harziasis. This disease is caused by a trematode parasite,
Schistosoma mansoni, which uses snails and humans as
hosts.
The recognition that copper has potent antibacterial prop-
erties followed and was well established in laboratory studies
(for a recent review see reference [30]). Some examples in-
clude the killing by means of copper or copper compounds
of Acinetobacter calcoaceticus/baumannii [31,32]; Bacillus
subtilis [32,33]; Bacillus macerans [34]; Campylobacter
jejuni [35]; Citrobacter [32]; Clostridium difficile [36,37];
Enterococci [11,12]; Escherichia coli [10-12,32,33,38-41];
Legionella pneumophila [31,42,43]; Listeria monocytogenes
[12,44-46]; Klebsiella pneumoniae [32]; Mycobacterium
tuberculosis [47]; Pseudomonas aeruginosa [48]; Pseudo-
monas fluorescens [45]; Pseudomonas striata [34]; Salmo-
nella sp. [12,32,35,39]; Salmonella typhimurium [45,49];
Shewanella putrefaciens [45]; Shigella flexnerii [32];
Staphylococcus epidermidis [50]; Staphylococcus aureus
[10-12,31-33,41,45,46,51,52]; and Streptococcus [32,53].
Recent studies have demonstrated that non-soluble copper
compounds, such as glass coated with thin films of CuO
[54], degradable phosphate glass fibres impregnated with
CuO [50,53] or metallic and copper alloys
[35,36,38,40,44,47,51,55,56] have potent biocidal properties,
even against difficult bacterial spores [36]. Interestingly,
bacteria exposed to metallic copper surfaces do not enter a
viable but nonculturable physiological state, in which they
are viable but do not multiply, but are completely inactivated
[44]. Importantly, based on the vast amount of antimicrobial
efficacy testing (180 tests, utilizing 3235 control and test
samples, conducted in independent microbiology laborato-
ries) sponsored by the Copper Development Association
(CDA), the U.S. Environmental Protection Agency (EPA)
has recently (March 2008) approved the registration of cop-
per alloys as materials with antimicrobial properties, thus
allowing the CDA to make public health claims [57]. The
following statement is included in the registration: "When
cleaned regularly, antimicrobial copper alloys surfaces kill
greater than 99.9% of bacteria within two hours, and con-
tinue to kill more than 99% of bacteria even after repeated
contamination". These public health claims acknowledge
that copper, brass and bronze are capable of killing harmful,
potentially deadly bacteria, such as Methicillin-resistant S.
aureus (MRSA). MRSA is one of the most virulent strains of
antibiotic-resistant bacteria and a common cause of hospital-
and community-acquired infections. Copper is the first solid
surface material to receive this type of EPA registration.
Copper demonstrates potent antiviral (virucidal) activity
as well. The inactivation of the following enveloped or
nonenveloped, single- or double-stranded DNA or RNA vi-
ruses by copper and copper compounds, has been reported:
bacteriophages [58-62], Infectious Bronchitis Virus [63],
Poliovirus [61,64], Junin Virus [59], Herpes Simplex Virus
[58,59], Human Immunodeficiency Virus Type 1 (HIV-1)
[11,65-67], West Nile Virus [11], Coxsackie Virus Types B2
& B4, Echovirus 4 and Simian Rotavirus SA11 [68]. More
recently, the inactivation of Influenza A [55,65], Rhinovirus
2, Yellow Fever, Measles, Respiratory Syncytial Virus,
Parainfluenza 3, Punta Toro, Pichinde, Adenovirus Type 1,
Cytomegalovirus and Vaccinia [65] has been demonstrated.
BIOCIDAL MECHANISMS OF COPPER
Copper exerts its toxicity to microorganisms through
several parallel mechanisms, which eventually may lead to
the microorganisms’ death even within minutes of their ex-
posure to copper (e.g. [14,38,65]). It is likely that the first
site that copper damages is the microorganisms’ envelope.
Recently, Nan Li and his colleagues [69], by using atomic
force microscopy, force-distance curves and inductively
coupled plasma mass spectrometer tests, studied the effects
of austenitic (a solid solution of ferric carbide or carbon in
iron) stainless steel containing or not containing copper on
the plasma membrane of E. coli. They found that the copper
containing steel adhered to the bacteria plasma membrane,
via the electrostatic forces exerted by Cu
2+
, to a significantly
greater extent than the austenitic stainless steel not contain-
ing copper. They reported that initial damage occurred to the
lipopolysaccharide patches on the outer plasma membrane,
which collapsed while the inner part of the bacteria remained
intact. Already in 1988, Ohsumi and colleagues reported that
Cu
2+
elicits significant permeability changes in intact Sac-
charomyces cerevisiae cells [14], which depending on the
plasma membrane fatty acid composition and the membrane
permeability, increased markedly in cells enriched with
polyunsaturated fatty acids [70]. Extensive copper-induced
disruption of membrane integrity inevitably leads to loss of
cell viability. However, even relatively small alterations in
the physical properties of biological membranes can elicit
marked changes in the activities of many essential mem-
brane-dependent functions, including transport protein activ-
ity and ion permeability [71].
While copper may interact with many microbial proteins
without damaging them, such as with copper chaperones
(e.g. [72,73]), copper may damage many proteins, both on
the microorganism envelope or within the cell, especially
when found in high concentrations, above the threshold by
which many microorganisms can cope with excess copper.
This may occur via displacement of essential metals from
their native binding sites in the proteins, or via direct interac-
tions with the proteins. In both cases, conformational
changes in the protein structure or in the protein active site
may occur, resulting in the inhibition or neutralization of the
protein biological activities. For example, specific oxidation
of the cysteine in the active site of vaccinia H1-related pro-
tein tyrosine phosphatase by Cu
2+
results in complete inacti-
274 Current Chemical Biology, 2009, Vol. 3, No. 3 Borkow and Gabbay
vation of the protein activity [74]. Another example is the
neutralization of HIV-1 protease, an essential protein for the
replication of the virus, by stoichiometric concentrations of
copper ions [75]. Direct inhibition by Cu
2+
required the pres-
ence of cysteine residue(s) in the protease [75,76]. Copper
also may mediate free radical attack of amino acids, espe-
cially of histidine and proline, causing substantial protein
alterations and even protein cleavage [77,78].
Copper ions can also damage nucleic acids. By cross
linking within and between strands of DNA [79] copper may
cause helical structure disorders and DNA denaturation [80].
In single-stranded DNA, such as that found in many DNA
viruses, a copper binding site was found on average in every
three nucleotides [81]. Guanine-specific covalent binding of
Cu
2+
in double stranded DNA was demonstrated following
crystallization (1.2-A resolution) of DNA soaked with cupric
chloride [82], explaining the observed specificity of Cu
2+
-
induced oxidative DNA damage that occurs near guanine
residues [83]. It has been suggested that subsequent to the
specific binding of copper to deoxyribonucleic acids, re-
peated cyclic redox reactions generate several OH radicals
near the binding site causing multiple damage to the nucleic
acids [84]. When examining the effects of Cu
2+
on purified
S. typhimurium DNA, DNA breakage occurred only when
the copper ions and H
2
O
2
were present, while no damage to
the DNA was detectable after incubation with the metal ions
alone or with H
2
O
2
alone [49], supporting the notion that
copper catalyzes the conversion of H
2
O
2
to hydroxyl radicals
[85], at least in vitro. Although copper binds DNA in vitro,
stronger competing ligands, such as glutathione and cysteine
[86,87], may remove copper away from the DNA in vivo.
Furthermore, recent studies using E. coli lacking copper ex-
port genes indicate that copper does not catalyze significant
oxidative DNA damage in vivo [86]. Electron paramagnetic
resonance spin trapping assays showed that the majority of
H
2
O
2
-oxidizable copper was located in the periplasm, away
from the DNA. However, it still may be that in some micro-
organisms, especially in viruses, copper oxidative damage to
the genetic material may occur through Fenton mechanisms.
Indirect toxic mechanisms have been suggested. For exam-
ple, exposure to high concentrations of copper may increase
the rate of H
2
O
2
generation [88], which could have acceler-
ated iron-mediated oxidative DNA damage [86].
In general, the redox cycling between Cu
2+
and Cu
1+
,
which can catalyze the production of highly hydroxyl radi-
cals, with subsequent damage to lipids, proteins, DNA and
other biomolecules [30,89], makes copper reactive and a
particularly effective antimicrobial. Other closely related
metals, such as zinc and nickel, do not readily undergo re-
dox-cycling reactions and are more stable in their various
cationic states. Zinc, which is an essential trace metal like
copper and well metabolized by humans, displays antifungal
properties [90]. Zinc pyrithione, for example, is widely used
as an antifouling agent in paints [91]. However, free zinc ion
in solution is highly toxic to plants, invertebrates, and even
to vertebrate fish [92] and in high dosage can promote oxida-
tive toxicity in humans [93]. Nickel, which also has potent
antimicrobial properties, is a known haematotoxic, immuno-
toxic, neurotoxic, genotoxic, nephrotoxic, hepatotoxic and
carcinogenic agent [94] and is therefore not used.
Many bacteria and fungi have different mechanisms to
deal with excess copper (reviewed in [30]). These include
exclusion by a permeability barrier, intra- and extra-cellular
sequestration by cell envelopes, active transport membrane
efflux pumps, reduction in the sensitivity of cellular targets
to copper ions, extracellular chelation or precipitation by
secreted metabolites including copper, and adaptation and
tolerance via upregulation of necessary genes in the presence
of copper (e.g. [95,96]). However, above a certain threshold
and time of exposure, which differs between the microorgan-
isms, they cannot deal with the copper overload and die. Due
to the multisite kill mechanism of copper and mostly non-
specific mechanisms of damage exerted by copper (see
above and [30]), their tolerance to copper is relatively low,
as compared to the resistance to antibiotics demonstrated by
some microorganisms (i.e., 10 fold lower sensitivity to cop-
per as opposed to 1000 fold less sensitivity to methicillin, for
example by methicillin resistant S. aureus). Thus, in contrast
to the highly resistant microbes that have evolved to antibiot-
ics in less than 50 years of use, tolerant microbes to copper
are extremely rare even though copper has been a part of the
earth for millions of years. Viruses do not have tolerance and
repair mechanisms, such as DNA repair mechanisms, as bac-
teria and fungi and thus are highly susceptible to copper in-
duced damage.
COPPER HEALTH RELATED APPLICATIONS
In contrast to the high susceptibility of microorganisms
to copper [30], copper is considered safe to humans, as dem-
onstrated by the widespread and prolonged use by women of
copper intrauterine devices [97-100]. The risk of adverse
reactions due to dermal contact with copper is considered
extremely low [101,102]. Copper is an essential trace ele-
ment involved in numerous human physiological and meta-
bolic processes [103,104], including in wound repair [105],
and many over-the-counter treatments for wound healing
contain copper [106,107]. The National Academy of Sci-
ences Committee established the U.S. Recommended Daily
Allowance of 0.9 mg of copper for normal adults [108].
Copper and copper-based compounds, due to their potent
biocidal properties, are now routinely used in several health-
related areas. These include 1) control of Legionella
[42,43,109-111] and other bacteria [112] in hospital water
distribution systems. Hospital-acquired Legionnaires' disease
has been reported from many hospitals since the first out-
break in 1976. Although cooling towers were linked to the
cases of Legionnaires' disease in the years after its discovery,
potable water has been the environmental source for almost
all reported hospital outbreaks [110,113]. Copper-silver ioni-
sation systems have emerged as the most successful long-
term disinfection method for hospital water disinfection sys-
tems [42,43,109-111]; 2) prevention of algae and other para-
sites growth in potable water reservoirs (e.g. [114,115]). The
efficacy of silver/copper/chlorine combinations in drinking
water for inactivation of protozoa such as Hartmannella
vermiformis and Naegleria fowleria [responsible for primary
amoebic meningoencephalitis] amoebas and Tetrahymena
pyriformis, is being explored [116,117]; 3) reduction of car-
ies in dentistry. Dental cements containing copper have been
shown to have antimicrobial and anticariogenic properties
[118,119]; 4) reduction of foodborne diseases through the
production and use of self-sterilizing metallic copper sur-
Copper Fighting Microbial, Fungal and Viral Infections Current Chemical Biology, 2009, Vol. 3, No. 3 275
faces [35,40,44,56] or materials containing copper
[11,12,53,54,120], in which the food is kept, handled or
transported. The addition of copper to drinking glasses has
been shown to reduce biofilm formation of Streptococcus
sanguis, thus reducing the risk of oral infections [53]. The
USA Centers for Disease Control (CDC) reported in 1999
that 76 million Americans (~25% of the population) suffer
from food poisoning annually. Recently they reported that
while several foodborne illnesses - yersinia, shigella, listeria,
sampylobacter, and shiga toxin-producing E. coli 0157 -
have become somewhat less common than they were in
1999, the overall rate of reported foodborne illness hasn't
budged much since 2004; and 5) in birth control by using
copper intrauterine contraceptive devices [100,121].
Novel uses of copper or copper-based compounds in
health-related applications are being explored and/or imple-
mented. One area is the reduction of transmission of health-
associated (nosocomial) pathogens in hospitals, clinics and
elderly homes, by i) making hospital hard surfaces, like door
knobs, bed rails, and intravenous stands, with metallic cop-
per [36,47,51,55] ii) making hospital soft surfaces, like
sheets, patient robes, patient pajamas, and nurse clothing,
from copper-impregnated biocidal textiles [11,12,122], and
iii) disinfecting contaminating cloths with copper-based bio-
cides [31].
Dust mites are considered to be an important source of
allergen for perennial rhinitis and asthmatic attacks [123].
Recently it was demonstrated that copper-impregnated fab-
rics are acaricidal [8,11]. Thus, elimination of house dust
mites in mattresses, quilts, carpets and pillows may improve
the quality of life of those suffering from dust-mite related
allergies.
The use of copper-impregnated socks for the prevention
and treatment of fungal foot infections (athlete’s foot) has
been reported [13,124]. Similarly, the use of copper oxide
containing wound dressings for the reduction of dressing and
wound contamination has shown excellent results in human
and animal studies, not only in reducing the contamination of
the wounds, but more importantly in enhancing and allowing
wound repair, especially of diabetic ulcers in which conven-
tional treatment modalities failed in closing the wounds (un-
published data).
A possible application of copper due to its potent viruci-
dal properties is its use in filtration devices that can deacti-
vate viruses in contaminated solutions, such as contaminated
blood products and breastmilk. Recently the deactivation of
HIV-1 and other viruses in suspension by copper-based fil-
ters has been reported [65,66].
The capacity to impregnate copper into different textile
products, as well as into latex and other polymeric materials
[10-12] allows for the production of personal protective
equipment (PPE) with antimicrobial and antiviral properties
to be used by first responders and laboratory personnel, who
may be exposed to pathogens. PPE such as gloves, masks
and disposable robes, may increase the safety not only of
those using these products but of the immediate environment
and assure safer disposal of the used items. Similarly, police
or health-workers uniforms that may be exposed to contami-
nated solutions, such as blood, would reduce the risk of
pathogens transmission.
In contrast to the above copper health related applica-
tions, copper is not appropriate for use for systemic infec-
tions, mainly since once copper is ingested it readily inter-
acts with transport proteins as well as small molecular
weight ligands [125,126], making it unavailable as an antim-
icrobial. Furthermore, in cases where no efficacious copper
metabolism occurs, the unligated free copper in the body
may be involved in disease pathogenesis, such as in Alz-
heimer's disease [127]. Another limitation of copper may be
the price of copper, which has recently escalated. However,
this is of special relevance mainly when whole surfaces or
products are made with copper or copper alloys. It is signifi-
cantly less prohibitive when copper compounds, such as
copper oxide, are impregnated in low percentages in medical
devices or other health related products. In any case, when
compared to the alternatives or the consequences of not us-
ing copper-containing products, e.g., increased nosocomial
infections and food poisoning and the related costs of treat-
ments, the issue of the copper cost is not significant.
In conclusion, the safety of copper to humans and its po-
tent biocidal properties allow the use of copper in many ap-
plications (Fig. (1)), including several that address medical
concerns of the greatest importance. While some of these
applications are already being amply used, novel possible
applications of copper may have a major effect on our lives.
CONFLICT OF INTEREST
G.B. is the Chief Medical Scientist of Cupron. J.G. is the
CEO of Cupron. Cupron is a company that uses copper oxide
in its medical and consumer applications.
ABBREVIATIONS
CDA = Copper Development Association
EPA = U.S. Environmental Protection Agency
Fig. (1). Current and future potential applications of copper and
copper compounds in different areas, which are based on copper’s
biocidal properties.
276 Current Chemical Biology, 2009, Vol. 3, No. 3 Borkow and Gabbay
MRSA = Methicillin-resistant Staphylococcus aureus
HIV-1 = Human Immunodeficiency Virus Type 1
PPE = Personal protective equipment
REFERENCES
[1] Dollwet HHA, Sorenson JRJ. Historic uses of copper compounds
in medicine. Trace Elements Med 2001; 2: 80-7.
[2] Foye Wo, Van De Workeen IB Jr, Matthes JD. Copper complexes
of aromatic dithiocarbamates and their antifungal activity. J Am
Pharm Assoc Am Pharm Assoc (Baltim) 1958; 47: 556-8.
[3] Scigliano JA, Grubb TC, Shay DE. Fungicidal testing of some
organocopper compounds. J Am Pharm Assoc Am Pharm Assoc
1950; 39: 673-6.
[4] Benns BG, Gingras BA, Bayley CH. Antifungal Activity of Some
Thiosemicarbazones and Their Copper Complexes. Appl Microbiol
1960; 8: 353-6.
[5] Belli N, Marin S, Sanchis V, Ramos AJ. Impact of fungicides on
Aspergillus carbonarius growth and ochratoxin A production on
synthetic grape-like medium and on grapes. Food Addit Contam
2006; 23: 1021-9.
[6] Kumbhar AS, Padhye SB, Saraf AP, Mahajan HB, Chopade BA,
West DX. Novel broad-spectrum metal-based antifungal agents.
Correlations amongst the structural and biological properties of
copper (II) 2- acetylpyridine N4-dialkylthiosemicarbazones. Biol
Met 1991; 4: 141-3.
[7] Gershon H, Clarke DD, Gershon M. Synergistic antifungal action
of 8-quinolinol and its bischelate with copper(II) and with mixed
ligand chelates composed of copper(II), 8- quinolinol, and aromatic
hydroxy acids. J Pharm Sci 1989; 78: 975-8.
[8] Mumcuoglu KY, Gabbay J, Borkow G. Copper oxide impregnated
fabrics for the control of house dust mites. Int J Pest Manag 2008;
54: 235-40.
[9] Lin MY, Huang KJ, Kleven SH. In vitro comparison of the activity
of various antifungal drugs against new yeast isolates causing
thrush in poultry. Avian Dis 1989; 33: 416-21.
[10] Borkow G, Gabbay J. Endowing textiles with permanent potent
biocidal properties by impregnating them with copper oxide.
JTATM 2006; 5: 1.
[11] Borkow G, Gabbay J. Putting copper into action: copper-
impregnated products with potent biocidal activities. FASEB J
2004; 18: 1728-30.
[12] Gabbay J, Mishal J, Magen E, Zatcoff RC, Shemer-Avni Y,
Borkow G. Copper oxide impregnated textiles with potent biocidal
activities. J Ind Textiles 2006; 35: 323-35.
[13] Zatcoff RC, Smith MS, Borkow G. Treatment of tinea pedis with
socks containing copper impregnated fibers. Foot 2008; 18: 136-41.
[14] Ohsumi Y, Kitamoto K, Anraku Y. Changes induced in the perme-
ability barrier of the yeast plasma membrane by cupric ion. J Bacte-
riol 1988; 170: 2676-82.
[15] Vagabov VM, Ivanov AY, Kulakovskaya TV, Kulakovskaya EV,
Petrov VV, Kulaev IS. Efflux of potassium ions from cells and
spheroplasts of Saccharomyces cerevisiae yeast treated with silver
and copper ions. Biochemistry (Mosc) 2008; 73: 1224-7.
[16] Weber DJ, Rutala WH. In: Block SS, Ed, Disinfection, Sterilization
and Preservation. New York, Lippincott Williams and Wilkins,
2001; 415-30.
[17] La Torre A, Talocci S, Spera G, Valori R. Control of downy mil-
dew on grapes in organic viticulture. Commun Agric Appl Biol Sci
2008; 73: 169-78.
[18] Gershon H. Antifungal activity of bischelates of 5-,7-, and 5,7-
halogenated 8- quinolinols with copper(II). Determination of ap-
proximate dimensions of the long and short axes of the pores in the
fungal spore wall. J Med Chem 1974; 17: 824-7.
[19]
Cheng TC, Guida VG, Butler MS, Howland KH. Use of copper
compounds in shellfish depuration and disease control in maricul-
ture. 2001; Incra Project NO. 262B: 31.
[20] Chandra S, Raizada S, Tyagi M, Gautam A. Synthesis, spectro-
scopic, and antimicrobial studies on bivalent nickel and copper
complexes of bis(thiosemicrbazone). Bioinorg Chem Appl 2007;
2007: 51483. doi:10.1155/2007/51483.
[21]
Schultz TP, Nicholas DD, Preston AF. A brief review of the past,
present and future of wood preservation. Pest Manag Sci 2007; 63:
784-8.
[22] 3M Industrial Mineral Products Division. The Schotchgard Algae
Resistant Roofing System. 2004. http://solutions.3m.com/wps/por-
tal/3M/en_US/IMPD/Roofing-Solutions/Products/Scotchgard-Algae-
Resistant/
[23] Cooney JJ, Tang RJ. Quantifying effects of antifouling paints on
microbial biofilm formation. Methods Enzymol 1999; 310: 637-44.
[24] Cooney TE. Bactericidal activity of copper and noncopper paints.
Infect Control Hosp Epidemiol 1995; 16: 444-50.
[25] UK Marine Sack Project. Copper-based antifouling paints. 2008.
http://www.ukmarinesac.org.uk/activities/ports/ph4_3_1.htm
[26] Oliveira-Filho EC, Lopes RM, Paumgartten FJ. Comparative study
on the susceptibility of freshwater species to copper-based pesti-
cides. Chemosphere 2004; 56: 369-74.
[27] Zidan ZH, Ragab FM, Mohamed KH. Molluscicidal activities of
certain pesticide and their mixtures against Biomphalaria alexan-
drina.
J Egypt Soc Parasitol 2002; 32: 285-96.
[28] Ragab F, Shoukry NM. Influence of certain fertilizers on the activ-
ity of some molluscicides against Biomphalaria alexandrina and
Lymnaea natalensis snails. J Egypt Soc Parasitol 2006; 36: 959-77.
[29] Hassan AA, Shoukary NM, Ismail NM. Efficacy of temperature,
and two commonly used molluscicides and fertilizers on Fasciola
gigantica eggs. J Egypt Soc Parasitol 2008; 38: 621-34.
[30] Borkow G, Gabbay J. Copper as a biocidal tool. Curr Med Chem
2005; 12: 2163-75.
[31] Gant VA, Wren MW, Rollins MS, Jeanes A, Hickok SS, Hall TJ.
Three novel highly charged copper-based biocides: safety and effi-
cacy against healthcare-associated organisms. J Antimicrob Che-
mother 2007; 60: 294-9.
[32] Cortes P, Atria AM, Contreras M, Garland MT, Pena O, Corsini G.
Magnetic properties and antibacterial activity of tetranuclear cop-
per complexes bridged by oxo group. J Chil Chem Soc 2006; 51:
957-60.
[33] Ruparelia JP, Chatterjee AK, Duttagupta SP, Mukherji S. Strain
specificity in antimicrobial activity of silver and copper nanoparti-
cles. Acta Biomater 2008; 4: 707-16.
[34] Chandra S, Raizada S, Tyagi M, Sharma PK. Spectroscopic and
biological approach of Ni(II) and Cu(II) complexes of 2-
pyridinecarboxaldehyde thiosemicarbazone. Spectrochim Acta A
Mol Biomol Spectrosc 2008; 69: 816-21.
[35] Faundez G, Troncoso M, Navarrete P, Figueroa G. Antimicrobial
activity of copper surfaces against suspensions of Salmonella en-
terica and Campylobacter jejuni. BMC Microbiol 2004; 4: 19-25.
[36] Weaver L, Michels HT, Keevil CW. Survival of Clostridium diffi-
cile on copper and steel: futuristic options for hospital hygiene. J
Hosp Infect 2008; 68: 145-51.
[37] Wheeldon LJ, Worthington T, Lambert PA, Hilton AC, Lowden
CJ, Elliott TS. Antimicrobial efficacy of copper surfaces against
spores and vegetative cells of Clostridium difficile: the germination
theory. J Antimicrob Chemother 2008; 62: 522-5.
[38] Espirito SC, Taudte N, Nies DH, Grass G. Contribution of copper
ion resistance to survival of Escherichia coli on metallic copper
surfaces. Appl Environ Microbiol 2008; 74: 977-86.
[39]
Ibrahim SA, Yang H, Seo CW. Antimicrobial activity of lactic acid
and copper on growth of Salmonella and Eschericia coli 0157:H7
in laboratory medium and carrot juice. Food Chemistry 2008; 109:
137-43.
[40] Noyce JO, Michels H, Keevil CW. Use of copper cast alloys to
control Escherichia coli O157 cross-contamination during food
processing. Appl Environ Microbiol 2006; 72: 4239-44.
[41] Ren G, Hu D, Cheng EW, Vargas-Reus MA, Reip P, Allaker RP.
Characterisation of copper oxide nanoparticles for antimicrobial
applications. Int J Antimicrob Agents 2009; 33(6): 587-90.
[42] Stout JE, Yu VL. Experiences of the first 16 hospitals using cop-
per-silver ionization for Legionella control: implications for the
evaluation of other disinfection modalities. Infect Control Hosp
Epidemiol 2003; 24: 563-8.
[43] Casari E, Ferrario A, Montanelli A. Prolonged effect of two com-
bined methods for Legionella disinfection in a hospital water sys-
tem. Ann Ig 2007; 19: 525-32.
[44] Wilks SA, Michels HT, Keevil CW. Survival of Listeria monocy-
togenes Scott A on metal surfaces: implications for cross-
contamination. Int J Food Microbiol 2006; 111: 93-8.
[45]
Russell SM. The effect of an acidic, copper sulfate-based commer-
cial sanitizer on indicator, pathogenic, and spoilage bacteria associ-
ated with broiler chicken carcasses when applied at various inter-
Copper Fighting Microbial, Fungal and Viral Infections Current Chemical Biology, 2009, Vol. 3, No. 3 277
vention points during poultry processing. Poult Sci 2008; 87: 1435-
40.
[46] Lopez-Carballo G, Hernandez-Munoz P, Gavara R, Ocio MJ. Pho-
toactivated chlorophyllin-based gelatin films and coatings to pre-
vent microbial contamination of food products. Int J Food Micro-
biol 2008; 126: 65-70.
[47] Mehtar S, Wiid I, Todorov SD. The antimicrobial activity of cop-
per and copper alloys against nosocomial pathogens and Mycobac-
terium tuberculosis isolated from healthcare facilities in the West-
ern Cape: an in vitro study. J Hosp Infect 2008; 68: 45-51.
[48] Harrison JJ, Turner RJ, Joo DA, et al. Copper and quaternary am-
monium cations exert synergistic bactericidal and antibiofilm activ-
ity against Pseudomonas aeruginosa. Antimicrob Agents Che-
mother 2008; 52: 2870-81.
[49] Keyhani E, Abdi-Oskouei F, Attar F, Keyhani J. DNA strand
breaks by metal-induced oxygen radicals in purified Salmonella ty-
phimurium DNA. Ann N Y Acad Sci 2006; 1091: 52-64.
[50] Neel EA, Ahmed I, Pratten J, Nazhat SN, Knowles JC. Characteri-
sation of antibacterial copper releasing degradable phosphate glass
fibres. Biomaterials 2005; 26: 2247-54.
[51] Noyce JO, Michels H, Keevil CW. Potential use of copper surfaces
to reduce survival of epidemic meticillin-resistant Staphylococcus
aureus in the healthcare environment. J Hosp Infect 2006; 63: 289-
97.
[52] Carson KC, Bartlett JG, Tan TJ, Riley TV. In vitro susceptibility of
methicillin-resistant Staphylococcus aureus and methicillin-
susceptible Staphylococcus aureus to a new antimicrobial, copper
silicate. Antimicrob Agents Chemother 2007; 51: 4505-7.
[53] Mulligan AM, Wilson M, Knowles JC. The effect of increasing
copper content in phosphate-based glasses on biofilms of Strepto-
coccus sanguis. Biomaterials 2003; 24: 1797-807.
[54] Ditta IB, Steele A, Liptrot C, et al. Photocatalytic antimicrobial
activity of thin surface films of TiO(2), CuO and TiO (2)/CuO dual
layers on Escherichia coli and bacteriophage T4. Appl Microbiol
Biotechnol 2008; 79: 127-33.
[55] Noyce JO, Michels H, Keevil CW. Inactivation of influenza A
virus on copper versus stainless steel surfaces. Appl Environ Mi-
crobiol 2007; 73: 2748-50.
[56] Wilks SA, Michels H, Keevil CW. The survival of Escherichia coli
O157 on a range of metal surfaces. Int J Food Microbiol 2005; 105:
445-54.
[57] Copper Development Association. U.S. EPA Approves Registra-
tion of Antimicrobial Copper Alloys. Copper Development Asso-
ciation 2008. http://www.copper.org/about/pressreleases/2008/pr-
2008_Mar_25.html
[58] Sagripanti JL. Metal-based formulations with high microbicidal
activity. Appl Environ Microbiol 1992; 58: 3157-62.
[59] Sagripanti JL, Routson LB, Lytle CD. Virus inactivation by copper
or iron ions alone and in the presence of peroxide. Appl Environ
Microbiol 1993; 59: 4374-6.
[60] Wong K, Morgan AR, Parachych W. Controlled cleavage of phage
R17 RNA within the virion by treatment with ascorbate and copper
(II). Can J Biochem 2001; 52: 950.
[61] Yahaya MT, Straub TM, Yahaya MT. Inactivation of poliovirus
and bacteriophage MS-2 in copper, galvanised and plastic domestic
water pipes. Int Copper Res Assoc 2001; Project 48.
[62] Yamamoto N, HIATT CW, Haller W. Mechanism of inactivation
of bacteriophages by metals. Biochim Biophys Acta 1964; 91: 257-
61.
[63] Jordan FT, Nassar TJ. The influence of copper on the survival of
infectious bronchitis vaccine virus in water. Vet Rec 1971; 89: 609-
10.
[64] Totsuka A, Otaki K. The effects of amino acids and metals on the
infectivity of poliovirus ribonucleic acid. Jpn J Microbiol 1974; 18:
107-12.
[65] Borkow G, Sidwell RW, Smee DF, et al. Neutralizing viruses in
suspensions by copper oxide based filters. Antimicrob Agents Che-
mother 2007; 51: 2605-7.
[66] Borkow G, Lara HH, Covington CY, Nyamathi A, Gabbay J. Deac-
tivation of human immunodeficiency virus type 1 in medium by
copper oxide-containing filters. Antimicrob Agents Chemother
2008; 52: 518-25.
[67]
Sagripanti JL, Lightfoote MM. Cupric and ferric ions inactivate
HIV. AIDS Res Hum Retroviruses 1996; 12: 333-7.
[68] The International Copper Association. Effects of copper and other
domestic plumbing materials on the survival of waterborne viruses.
2004. http://www.copperinfo.com.
[69] Nan L, Liu Y, Lu M, Yang K. Study on antibacterial mechanism of
copper-bearing austenitic antibacterial stainless steel by atomic
force microscopy. J Mater Sci Mater Med 2008; 19: 3057-62.
[70] Avery SV, Howlett NG, Radice S. Copper toxicity towards Sac-
charomyces cerevisiae: dependence on plasma membrane fatty acid
composition. Appl Environ Microbiol 1996; 62: 3960-6.
[71] Hazel JR, Williams EE. The role of alterations in membrane lipid
composition in enabling physiological adaptation of organisms to
their physical environment. Prog Lipid Res 1990; 29: 167-227.
[72] Hussain F, Sedlak E, Wittung-Stafshede P. Role of copper in fold-
ing and stability of cupredoxin-like copper-carrier protein CopC.
Arch Biochem Biophys 2007; 467: 58-66.
[73] Hussain F, Wittung-Stafshede P. Impact of cofactor on stability of
bacterial (CopZ) and human (Atox1) copper chaperones. Biochim
Biophys Acta 2007; 1774: 1316-22.
[74] Kim JH, Cho H, Ryu SE, Choi MU. Effects of metal ions on the
activity of protein tyrosine phosphatase VHR: highly potent and
reversible oxidative inactivation by Cu2+ ion. Arch Biochem Bio-
phys 2000; 382: 72-80.
[75] Karlstrom AR, Levine RL. Copper inhibits the protease from hu-
man immunodeficiency virus 1 by both cysteine-dependent and
cysteine-independent mechanisms. Proc Natl Acad Sci USA 1991;
88: 5552-6.
[76] Karlstrom AR, Shames BD, Levine RL. Reactivity of cysteine
residues in the protease from human immunodeficiency virus: iden-
tification of a surface-exposed region which affects enzyme func-
tion. Arch Biochem Biophys 1993; 304: 163-9.
[77] Davies MJ, Gilbert BC, Haywood RM. Radical-induced damage to
proteins: e.s.r. spin-trapping studies. Free Radic Res Commun
1991; 15: 111-27.
[78] Dean RT, Wolff SP, McElligott MA. Histidine and proline are
important sites of free radical damage to proteins. Free Radic Res
Commun 1989; 7: 97-103.
[79] Rifkind JM, Shin YA, Hiem JM, Eichorn GL. Co-operative disor-
dering of single stranded polynucleotides through copper crosslink-
ing. Biopolymers 2001; 15: 1879.
[80] Martin RB, Mariam YH. Metal Ions in Solution. Marcel Dekker:
New York, 2001.
[81] Sagripanti JL, Goering PL, Lamanna A. Interaction of copper with
DNA and antagonism by other metals. Toxicol Appl Pharmacol
1991; 110: 477-85.
[82] Geierstanger BH, Kagawa TF, Chen SL, Quigley GJ, Ho PS. Base-
specific binding of copper(II) to Z-DNA. The 1.3-A single crystal
structure of d(m5CGUAm5CG) in the presence of CuCl2. J Biol
Chem 1991; 266: 20185-91.
[83] Sagripant JL, Kraemer KH. Site-specific oxidative DNA damage at
polyguanosines produced by copper plus hydrogen peroxide. J Biol
Chem 1989; 264: 1729-34.
[84] Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal
ions. Free Radic Biol Med 1995; 18: 321-36.
[85] Gunther MR, Hanna PM, Mason RP, Cohen MS. Hydroxyl radical
formation from cuprous ion and hydrogen peroxide: a spin-trapping
study. Arch Biochem Biophys 1995; 316: 515-22.
[86] Macomber L, Rensing C, Imlay JA. Intracellular copper does not
catalyze the formation of oxidative DNA damage in Escherichia
coli. J Bacteriol 2007; 189: 1616-26.
[87] Schrammel A, Koesling D, Gorren AC, Chevion M, Schmidt K,
Mayer B. Inhibition of purified soluble guanylyl cyclase by copper
ions. Biochem Pharmacol 1996; 52: 1041-5.
[88] Manzl C, Enrich J, Ebner H, Dallinger R, Krumschnabel G. Cop-
per-induced formation of reactive oxygen species causes cell death
and disruption of calcium homeostasis in trout hepatocytes. Toxi-
cology 2004; 196: 57-64.
[89] Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative
stress. Curr Med Chem 2005; 12: 1161-208.
[90] Rieth H. [Killing of pathogenic fungi with organic zinc com-
pounds. Fungicidal aerosol disinfection and accumulative impreg-
nation]. Mykosen 1968; 11: 667-70.
[91]
Konstantinou IK, Albanis TA. Worldwide occurrence and effects
of antifouling paint booster biocides in the aquatic environment: a
review. Environ Int 2004; 30: 235-48.
[92]
Eisler R. Zinc Hazard to Fish, Wildlife, and Invertebrates: A Syn-
optic Review" Contaminant Hazard Reviews (Laurel, Maryland:
278 Current Chemical Biology, 2009, Vol. 3, No. 3 Borkow and Gabbay
U.S. Department of the Interior, Fish and Wildlife Service). 1993.
http://www.pwrc.usgs.gov/infobase/eisler/chr_26_zinc.pdf
[93] Wright RO, Baccarelli A. Metals and neurotoxicology. J Nutr
2007; 137: 2809-13.
[94] Das KK, Das SN, Dhundasi SA. Nickel, its adverse health effects
& oxidative stress. Indian J Med Res 2008; 128: 412-25.
[95] Bersch B, Favier A, Schanda P, et al. Molecular structure and
metal-binding properties of the periplasmic CopK protein ex-
pressed in Cupriavidus metallidurans CH34 during copper chal-
lenge. J Mol Biol 2008; 380: 386-403.
[96] Magnani D, Barre O, Gerber SD, Solioz M. Characterization of the
CopR regulon of Lactococcus lactis IL1403. J Bacteriol 2008; 190:
536-45.
[97] Anonymous. Copper IUDs, infection and infertility. Drug Ther
Bull 2002; 40: 67-9.
[98] Bastianelli C, Farris M, Benagiano G. Emergency contraception: a
review. Eur J Contracept Reprod Health Care 2008; 13: 9-16.
[99] Bilian X. Intrauterine devices. Best Pract Res Clin Obstet Gynaecol
2002; 16: 155-68.
[100] O'Brien PA, Kulier R, Helmerhorst FM, Usher-Patel M, d'Ar-
cangues C. Copper-containing, framed intrauterine devices for con-
traception: a systematic review of randomized controlled trials.
Contraception 2008; 77: 318-27.
[101] Hostynek JJ, Maibach HI. Copper hypersensitivity: dermatologic
aspects--an overview. Rev Environ Health 2003; 18: 153-83.
[102] Gorter RW, Butorac M, Cobian EP. Examination of the cutaneous
absorption of copper after the use of copper-containing ointments.
Am J Ther 2004; 11: 453-8.
[103] Olivares M, Uauy R. Copper as an essential nutrient. Am J Clin
Nutr 1996; 63: 791S-6S.
[104] Uauy R, Olivares M, Gonzalez M. Essentiality of copper in hu-
mans. Am J Clin Nutr 1998; 67: 952S-9S.
[105] Borkow G, Gabbay J, Zatcoff RC. Could chronic wounds not heal
due to too low local copper levels? Med Hypotheses 2008; 70: 610-
3.
[106] Pereira CE, Felcman J. Correlation between five minerals and the
healing effect of Brazilian medicinal plants. Biol Trace Elem Res
1998; 65: 251-9.
[107] Schlemm DJ, Crowe MJ, McNeill RB, Stanley AE, Keller SJ.
Medicinal yeast extracts. Cell Stress Chaperones 1999; 4: 171-6.
[108] Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference in-
takes: vitamin A, vitamin K, arsenic, boron, chromium, copper, io-
dine, iron, manganese, molybdenum, nickel, silicon, vanadium, and
zinc. J Am Diet Assoc 2001; 101: 294-301.
[109] Chen YS, Lin YE, Liu YC, et al. Efficacy of point-of-entry copper-
-silver ionisation system in eradicating Legionella pneumophila in
a tropical tertiary care hospital: implications for hospitals contami-
nated with Legionella in both hot and cold water. J Hosp Infect
2008; 68: 152-8.
[110] Sabria M, Yu VL. Hospital-acquired legionellosis: solutions for a
preventable infection. Lancet Infect Dis 2002; 2: 368-73.
[111] Cachafeiro SP, Naveira IM, Garcia IG. Is copper-silver ionisation
safe and effective in controlling legionella? J Hosp Infect 2007; 67:
209-16.
[112] Huang HI, Shih HY, Lee CM, Yang TC, Lay JJ, Lin YE. In vitro
efficacy of copper and silver ions in eradicating Pseudomonas
aeruginosa, Stenotrophomonas maltophilia and Acinetobacter
baumannii: implications for on-site disinfection for hospital infec-
tion control. Water Res 2008; 42: 73-80.
[113] Lin Yu, Vidic R, Stout JE, Yu VL. Legionella in water distribution
systems. JAWWA 2001; 90: 112-21.
[114] Applied Biochemist Company. Products for Water Quality. 2008.
http://www.appliedbiochemists.com/products/clearigate.htm
[115] SePro Company. Captain Liquid Copper Algaecide. 2008.
http://www.sepro.com/default.php?page=captain
[116] Rohr U, Weber S, Selenka F, Wilhelm M. Impact of silver and
copper on the survival of amoebae and ciliated protozoa in vitro.
Int J Hyg Environ Health 2000; 203: 87-9.
[117] Hambidge A. Reviewing efficacy of alternative water treatment
techniques. Health Estate 2001; 55: 23-5.
[118] Mahler DB. The high-copper dental amalgam alloys. J Dent Res
1997; 76: 537-41.
[119] Thneibat A, Fontana M, Cochran MA, et al. Anticariogenic and
antibacterial properties of a copper varnish using an in vitro micro-
bial caries model. Oper Dent 2008; 33: 142-8.
[120] Soto M, Chavez G, Baez M, Martinez C, Chaidez C. Internalization
of Salmonella typhimurium into mango pulp and prevention of fruit
pulp contamination by chlorine and copper ions. Int J Environ
Health Res 2007; 17: 453-9.
[121] Fantasia HC. Options for intrauterine contraception. J Obstet Gy-
necol Neonatal Nurs 2008; 37: 375-83.
[122] Borkow G, Gabbay J. Biocidal textiles can help fight nosocomial
infections. Med Hypotheses 2008; 70: 990-4.
[123] Brunton SA, Saphir RL. Dust mites and asthma. Hosp Pract (Off
Ed) 1999; 34: 67-76.
[124] Zatcoff RC. HealthStide
TM
Socks - Footware to a higher standard.
Podiatry Management 2005; November/December: 202-3.
[125] Harris ED, Qian Y, Reddy MC. Genes regulating copper metabo-
lism. Mol Cell Biochem 1998; 188: 57-62.
[126] Krupanidhi S, Sreekumar A, Sanjeevi CB. Copper & biological
health. Indian J Med Res 2008; 128: 448-61.
[127] Brewer GJ. The risks of free copper in the body and the develop-
ment of useful anticopper drugs. Curr Opin Clin Nutr Metab Care
2008; 11: 727-32.
Received: December 18, 2008 Revised: April 08, 2009 Accepted: April 24, 2009
... Cu and its complexes are popular for their biocidal properties since ancient times. The earliest record of Cu being used for medicinal application can be found in Smith Papyrus, an ancient Egyptian medical text composed during 2600 to 2200 B.C.; it describes the use of Cu to sterilize chest wounds and drinking water (Borkow and Gabbay 2009). The doses required for the treatment of bacterial infections, however, are reasonably high enough to cause concomitant damage to healthy surrounding cells as well. ...
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Besides synthetic drugs, a wide variety of medicinal plants have been used for the prevention and management of various liver disorders. Generally, plant therapies are well tolerated due to their lesser side effects. The aims and objectives of this review are to describe the drug therapies used for treating liver disorders as well as the most commonly used hepatoprotective plant-derived bioactive ingredients and their formulations employed for treating various liver pathologies. The extensive literature review was conducted using different databases such as ScienceDirect, SciFinder Scholar, Wiley Online Library, PubMed, ResearchGate, Google Scholar and Chemical Abstracts (until March 2021). Our literature searches showed that a wide array of plant products or plant extracts have been used in the folklore and traditional remedies for the prevention and management of liver disorders. The complex chemical structures of many isolated plant ingredients such as flavonoids, polyphenols, and steroid-type compounds have been determined using sophisticated analytical techniques. While the pharmacological and toxicological activities of many plant products have been tested in animal models, their underlying mechanism of action remains unknown. In this review, we will describe the hepatoprotective actions of the following plants and their bioactive components: Allium sativum, Allium hirtifolium, Andrographis paniculata, Apium graveolens, Asparagus racemosus, Berberis vulgaris, Curcuma longa, Emblica officinalis, Glycyrrhiza glabra, Marrubium vulgare, Nigella sativa, Phyllanthus niruri, Picrorhiza kurroa, Solanum nigrum, Swertia chirayita, Taraxacum officinale, oleanolic acid, Cliv-92, ursolic acid, berberine, proanthocyanidins, naringenin, silymarin, andrographolide, glycyrrhizin, curcumin, rhein, geniposide and resveratrol. There are challenges and opportunities for understanding the mechanism of action of the phytotherapies used for curing liver diseases as well as discovering new drug molecules useful for targeting different liver ailments. Combinations of traditional herbal remedies found to be safe and effective are also suggested as a possible cost-effective therapeutic tool to be tested in future researches aiming to unveil novel options to treat liver disorders in humans. However, well-designed, randomized, placebo-controlled, multicentre trials are needed to establish the long-term safety and efficacy as well the optimal dose schedules required for treating different liver disorders in humans.
... The Aztecs used copper oxide for treating skin conditions, and copper sulphate was used in Africa and Asia for healing sores and skin diseases. [16] Copper is a b-stabilizer, and the addition of Cu decreases the melting point of the Ti-Cu alloy. [17] Silver behaves similarly to Cu in Ti-alloys, although it is too expensive to use in industrial applications, [18] and it is not a strong b-stabilizer. ...
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One of the major issues with dental implants is failure due to bacterial infection, and additions of copper are known to improve the antimicrobial properties of Ti alloys. There are inconsistencies in the Ti rich area of the Cu-Ti binary phase diagram, hence the need to find out if Ti2Cu or Ti3Cu is formed, and to identify the type of formation of Ti2Cu. Four alloys: 20, 33, 40 and 50 Cu (mass%) were produced by arc melting and studied using SEM, XRD and DSC. The reactions were derived, and the temperatures of the reactions were determined by DSC. The formation of Ti2Cu is congruent, and no Ti3Cu was found.
... The membrane transporters and metal regulation systems vary depending on the organism, and, therefore, the critical level of a given metal ion is different for bacteria and mammals. Some metals, such as Cu and Ag, have a long-standing history as 2 of 15 antimicrobial agents [6,7], and they are, still, broadly used nowadays in medical devices [8] (for example as catheters, bandages, wound dressing) and food packaging [9]. In the context of antimicrobial resistance, metal-ion salts, metallic surfaces, and metal nanoparticles, currently, are regaining interest as antibacterial compounds. ...
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The development of antimicrobial devices and surfaces requires the setup of suitable materials, able to store and release active principles. In this context, zeolites, which are microporous aluminosilicate minerals, hold great promise, since they are able to serve as a reservoir for metal-ions with antimicrobial properties. Here, we report on the preparation of Linde Type A zeolites, partially exchanged with combinations of metal-ions (Ag+, Cu2+, Zn2+) at different loadings (0.1–11.9 wt.%). We combine X-ray fluorescence, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction to monitor the metal-ion contents, distribution, and conservation of the zeolite structure after exchange. Then, we evaluate their antimicrobial activity, using agar dilution and optical-density monitoring of Escherichia coli cultures. The results indicate that silver-loaded materials are at least 70-fold more active than the copper-, zinc-, and non-exchanged ones. Moreover, zeolites loaded with lower Ag+ concentrations remain active down to 0.1 wt.%, and their activities are directly proportional to the total Ag content. Sequential exchanges with two metal ions (Ag+ and either Cu2+, Zn2+) display synergetic or antagonist effects, depending on the quantity of the second metal. Altogether, this work shows that, by combining analytical and quantitative methods, it is possible to fine-tune the composition of bi-metal-exchanged zeolites, in order to maximise their antimicrobial potential, opening new ways for the development of next-generation composite zeolite-containing antimicrobial materials, with potential applications for the design of dental or bone implants, as well as biomedical devices and pharmaceutical products.
... Recent research interest in antimicrobial agents focuses on Cu due to its biocidal effect against a wide range of pathogens, including bacteria, fungi, and viruses [6], that even extends to methicillin-resistant Staphylococcus aureus (MRSA) [7] and vancomycin-resistant Enterococcus [1]. Acknowledging the high therapeutic potential of copper, Cu-based products have been approved by the US Environmental Protection Agency since February 2008 for human use [8]. ...
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Osteomyelitis is an inflammation of the bone caused by bacterial infection. It usually develops from broken bones, decayed teeth, or heavily punctured wounds. Multi-drug-resistant bacteria are the major hurdle in the treatment of osteomyelitis. The ever-rising antibiotic resistance even leads to amputations or fatalities as a consequence of chronic osteomyelitis. Hence, a single agent with antibacterial activity as well as bone regenerative properties can serve as a potential off-the-shelf product in the treatment of osteomyelitis. Herein, the antibacterial and pro-osteogenic characteristics of copper sericin (Cu-SER) metal–organic frameworks (MOFs) are reported. Sericin, a silk protein with antibacterial activity and an osteoinduction property, acts as an organic template for the deposition of Cu-SER MOFs, similar to collagen during biomineralization in bone. The MOFs exhibit cytocompatibility and osteogenic activity in a dose-dependent manner, as revealed by cell proliferation (alamarBlue) and mineralization (Alizarin Red S and Energy Dispersive X-Ray analysis). The bactericidal activity of Cu-SER MOFs was investigated by scanning electron microscopy and a growth kinetic analysis. Together, the report illuminates the unique phenomenon of Cu-SER MOFs that kill bacteria upon contact while being well-tolerated by primary human cells. Hence, Cu-SER MOFs hold the potential to minimize antibiotic dependence.
... For centuries, copper ions were used to disinfect solids, liquid and human tissue, whether alone or in copper complexes. [10] Copper and copper compounds having very good biocide properties as such they can be used as antifungal, antiviral agents and antibacterial and can be emphasised on novel health related aspects also [11][12] . Copper's fungicidal properties were demonstrated in controlled lab experiments beginning in the early 1950s [13][14] and since then, copper and copper compounds have been shown to eventually destroy a wide range of pathogen. ...
Article
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The concept of Vrana was elaborated in 1000 BC by Sushruta the father of Indian surgery. Sushruta explained thoroughly sixty types of wound management procedures to achieve the goal of fast wound healing. He has suggested numerous herbal drugs that can be used as local application. He introduces to technique that broadly classified as Vrana Ropana (wound healing) and Vrana Shodhana (wound cleaning). Wound healing had always been challenging to the wound care experts in all era be it ancient or now. The wound healing process is really complex, by which normal anatomy and function have to be restored as before. This comprises mainly 4 phases as haemostasis, inflammation, proliferation and remodelling with respect of order of occurrence. By using herbal medication, we can accelerate wound healing process.
... [6] Importantly, copper-based compounds have biocidal properties and thus several health-related applications. [22,23] Several methods such as thermal oxidation, [24] sonochemical, [25] combustion, [26] quick-precipitation, [27,28] and microwave irradiation [29] have been used to produce CuO nanoparticles with various shapes, including nano-wires, nano-rods, nano-needles, and nanoparticles. Besides these methods, electrochemical processing is another cost-effective, efficient method to produce small-scale copper nanoparticles. ...
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This special Issue is to create collections of Articles on specific topics. The aim is to build a community of authors and readers to discuss the latest research and develop new ideas and research directions.The articles in this issue are led by Editors who are experts in the subject and oversee the editorial process for papers.This provide a great platform to promote the break through research works.The potentially advanced special issue focussing on biomedical application from branches of life science, Chemistry andPhysics . This special issue is a join collaboration between Dhanalakshimi srinivasan College of Arts & Science for women Autonomous & International journal of Life Science & Pharma Research. This Provide a platform for the researchers to publish their innovative research findings.It was discussed Antibacterial ,Antifungal, Anticancer, Antioxidant and Anticonventional activities..It also included papers on phytochemical screening and pharmaceutical activity of medicinal plants andalso focused on biosynthesis of Nanomaterials and its Biological applications.The papers in this special issue broadly divided into the applications of Microbiology, Biotechnology,Biochemistry ,Chemistry and Physics.
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Microbial resistance to the antibiotics is a serious problem at present and will become alarming in near future. It is therefore important to establish a new technology that has antibacterial potential without developing resistance against bacterial strains. Nanotechnology has come to a way forward to address these antimicrobial challenges. Metal-based engineered nanomaterials (ENMs) are the main core of nanotechnology. Development in the field of metal-based ENMs has shown the potential to use it as an antimicrobial agent. The current chapter will critically evaluate the potential of metal-based ENMs as antimicrobial agents. This will include their fabrication process, properties, interaction with bacteria, and mode of action and mechanistic view of bacterial killing.
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Natural polysaccharides are critical to a wide range of fields (e.g., medicine, food production, and cosmetics) for their various remarkable physical properties and biological activities. However, the bioactivities of naturally acquired polysaccharides may be unsatisfactory and limit their further applications. It is generally known that the chemical structure exhibited by polysaccharides lays the material basis for their biological activities. Accordingly, possible structural modifications should be conducted on polysaccharides for their enhancement. Recently, polysaccharides complexed with metal ions (e.g., Fe, Zn, Mg, Cr, and Pt) have been reported to be possibly used to improve their bioactivities. Moreover, since the properties exhibited by metal ions are normally conserved, polysaccharides may be endowed with new applications. In this review, the synthesis methods, characterization methods, and bioactivities of polysaccharide metal complexes are summarized specifically. Then, the application prospects and limitations of these complexes are analyzed and discussed.
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The biochemical basis for the essentiality of copper, the adequacy of the dietary copper supply, factors that condition deficiency, and the special conditions of copper nutriture in early infancy are reviewed. New biochemical and crystallographic evidence define copper as being necessary for structural and catalytic properties of cuproenzymes. Mechanisms responsible for the control of cuproprotein gene expression are not known in mammals; however, studies using yeast as a eukaryote model support the existence of a copper-dependent gene regulatory element. Diets in Western countries provide copper below or in the low range of the estimated safe and adequate daily dietary intake. Copper deficiency is usually the consequence of decreased copper stores at birth, inadequate dietary copper intake, poor absorption, elevated requirements induced by rapid growth, or increased copper losses. The most frequent clinical manifestations of copper deficiency are anemia, neutropenia, and bone abnormalities. Recommendations for dietary copper intake and total copper exposure, including that from potable water, should consider that copper is an essential nutrient with potential toxicity if the load exceeds tolerance. A range of safe intakes should be defined for the general population, including a lower safe intake and an upper safe intake, to prevent deficiency as well as toxicity for most of the population.
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Escherichia coli O157:H7 is a serious pathogen causing haemorrhagic colitis. It has been responsible for several large-scale outbreaks in recent years. E. coli O157:H7 is able to survive in a range of environments, under various conditions. The risk of infection from contaminated surfaces is recognised, especially due to the low infectious dose required. In this study, a high concentration (107 cells) of E. coli O157 was placed onto different metals and survival time measured. Results showed E. coli O157 to survive for over 28 days at both refrigeration and room temperatures on stainless steel. Copper, in contrast, has strong antibacterial properties (no bacteria can be recovered after only 90 min exposure at 20 °C, increasing to 270 min at 4 °C) but its poor corrosion resistance and durability make it unsuitable for use as a surface material. Other copper-containing alloys, such as copper nickels and copper silvers, have improved durability and anticorrosion properties and greatly reduce bacterial survival times at these two temperatures (after 120 min at 20 °C and 360 min at 4 °C, no E. coli could be detected on a copper nickel with a 73% copper content). Use of a surface material with antibacterial properties could aid in preventing cross-contamination events in food processing and domestic environments, if standard hygiene measures fail.
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TiO(2)-coated surfaces are increasingly studied for their ability to inactivate microorganisms. The activity of glass coated with thin films of TiO(2), CuO and hybrid CuO/TiO(2) prepared by atmospheric Chemical Vapour Deposition (Ap-CVD) and TiO(2) prepared by a sol-gel process was investigated using the inactivation of bacteriophage T4 as a model for inactivation of viruses. The chemical oxidising activity was also determined by measuring stearic acid oxidation. The results showed that the rate of inactivation of bacteriophage T4 increased with increasing chemical oxidising activity with the maximum rate obtained on highly active sol-gel preparations. However, these were delicate and easily damaged unlike the Ap-CVD coatings. Inactivation rates were highest on CuO and CuO/TiO(2) which had the lowest chemical oxidising activities. The inactivation of T4 was higher than that of Escherichia coli on low activity surfaces. The combination of photocatalysis and toxicity of copper acted synergistically to inactivate bacteriophage T4 and retained some self-cleaning activity. The presence of phosphate ions slowed inactivation but NaCl had no effect. The results show that TiO(2)/CuO coated surfaces are highly antiviral and may have applications in the food and healthcare industries.
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Impregnation or coating of cotton and polyester fibers with cationic copper endows them with potent broad-spectrum antibacterial, antiviral, antifungal, and antimite properties (Borkow, G. and Gabbay, J. (2004). Putting Copper into Action: Copper-impregnated Products with Potent Biocidal Activities, FASEB Jounal, 18(14): 1728-1730). This durable platform technology enables the mass production of woven and non-woven fabrics, such as sheets, pillow covers, gowns, socks, air filters, mattress covers, carpets, etc. without the need of altering any industrial procedures or machinery, but only the introduction of copper oxide-treated fibers. The biocidal properties of fabrics containing 3-10% copper-impregnated fibers are permanent, are not affected by extreme washing conditions, and do not interfere with the manipulation of the final products (e.g., color, press, etc.). In this article, the authors describe data showing that (i) antifungal socks containing 10% w/w (weight/weight) copper-impregnated fibers alleviate athlete’s foot; (ii) antimicrobial fabrics (sheets) containing 10% (w/w) copper-impregnated fibers decrease bacterial colonization in a clinical setting; and (iii) these products do not have skin-sensitizing properties or any other adverse effects. Taken together, these results demonstrate the wide preventive and curative potential of copper oxide-impregnated apparel products.
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Copper oxide (CuO) has broad-spectrum anti-microbial and anti-fungal properties. The aim of this study was to test the acaricidal efficacy of CuO-impregnated fabrics on the common house dust mite, Dermatophagoides farinae. The overall vitality/mobility of the mites was reduced when they were exposed to the CuO-impregnated fabrics and, when possible, the dust mites migrated to fabrics where no CuO was present. The mortality of mites exposed for 10 days to fabrics containing 0.2% (w/w) CuO was significantly higher than the mortality of mites on control fabrics (72 ± 4 and 18.9 ± 0.3%, respectively). The mortality reached 95.4 and 100% with fabrics containing 0.4 and 2% CuO after 47 and 5 days, respectively. The acaricidal effect of copper oxide seems to be due to direct toxicity. The use of fabrics containing copper oxide may thus be an important avenue for reducing house dust mite populations, and for reducing the load of dust mite allergens.
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This treatise reviews medical uses of various forms of copper recorded throughout the history of mankind. Ancient Egyptian papyri, Greek, Roman, Aztec, Hindu, and Persian writings as well as medieval and subsequent European medical literature record various consistent medical uses of copper. There are many reported uses of copper and its compounds as antibacterial, antiinflammatory, antiarrhythmic, antitumor, and antiepileptic agents. Copper was also recommended to promote wound healing and heal broken bones. Tracing the development of folk medicine and the many rediscoveries of the beneficial effects of copper compounds leads to the suggestion that serious consideration should be given to modern-day medical uses of complexes of this essential metalloelement.
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Polychlorinated dibenzo-para-dioxins (PCDDs) are present as trace impurities in various manufactured chemicals and in combustion products. The chemical and environmental stability of PCDDs and their tendency to accumulate in fatty tissues have resulted in their widespread detection throughout the global ecosystem. The most toxic and extensively studied PCDD isomer is 2,3,7,8-tetrachlorodibenzo-para-dioxin (2,3,7,8-TCDD). Accidental contamination of the environment by 2,3,7,8-TCDD has resulted in deaths in many species of birds, wildlife, and domestic animals, and in the closing of rivers to fishing due to high residues in fish, i.e., >50 parts per trillion (ppt) wet weight. Laboratory studies with birds, mammals, aquatic organisms, and other species have conclusively demonstrated that exposure to 2,3,7,8-TCDD can be associated with acute and delayed mortality, carcinogenic, teratogenic, reproductive, mutagenic, histopathologic, and immunotoxic effects.