Very interesting article. However, I don't think it concerns colloidal silver though. All the research is being done on Ag+ ions, which although present in most CS, is not the part of the CS which has the real punch. It has been shown that metallic silver, not silver ions, are the real workhorses in CS, being many times as effective as Ag+ in killing pathogens.
All the resistance they found is for Ag+. The pumps and so forth just are not going to work with the actual colloidal part of CS (heck, if they did anything they would pump the wrong way since CS is of the opposite charge as the ions). They seem to be very confused on the issue and the difference between silver metal and silver ions which is substantial. For the most part they are using and tesing against ions, but claiming that exposure of pathogens to metal will cause resistance. I don't see how with the resistance mechanisms they show this could be the case. Marshall Terry Chamberlin wrote: > For the technical-minded listers, you should peruse > this: > > Silver cations as an antimicrobial agent: clinical > uses and bacterial resistance > > Simon Silver, Jeng-Fan Lo and Amit Gupta > Department of Microbiology and Immunology, University > of Illinois, Chicago, Illinois, USA > > Silver cations (Ag+) are important, often > misunderstood compounds that play a significant role > as effective and legitimate antimicrobial agents, used > particularly in the treatment of burns. Their spectrum > of uses is broad and generally unfamiliar, ranging > from beneficial clinical applications, to commercial- > and folk-practices that are of questionable value but > of little harm, to "snake oil" products and frauds > found through the internet and in health food stores. > > In an effort to better understand and anticipate the > uses of these compounds, we recently studied > plasmid-mediated resistance to silver. (1) Advances in > molecular genetics have allowed us to use > epidemiological tools to establish the range and > diversity of resistance systems. Past difficulties in > measuring Ag+ resistance have been overcome. (2) The > importance of the halide concentration and initial > cell number in such measurements has been shown, and > after the sequence of the first silver resistance gene > cluster was complete, (1) we found closely homologous > genetic determinants surprisingly abundant in hospital > collections of enteric bacteria, both from > silver-exposed and not-knowingly silver-exposed > sources (A. Gupta et al., in prep.). > > Clinical Uses of Silver Products > Silver cations are microcidal at low concentrations, > and are without serious side effects for humans. > Argyria (irreversible discoloration of the skin > resulting from subepithelial silver deposits) is rare > and mostly of cosmetic concern. The widest and > best-known medicinal use of silver preparations is as > preferred antimicrobial agents for the treatment of > serious burns. (3) Silver sulfadiazine cream that > contains 1% silver sulfadiazine plus 0.2% > chlorhexidine digluconate is the mostly widely used > product, marketed as Silvazine in the United States > for human and veterinary use. Flamazine is the same > product in other countries, largely in the United > Kingdom, Canada and continental Europe. Ag-coated > nylon is increasingly being used to cover burn wounds > and traumatic injuries to humans4 and large animals. > (5) Silver sulfadiazine-coated methacrylate sheet > material that provides a stable base for sustained > release of Ag+ over days is also being investigated. > (6) These silver-containing fabrics are easier to > apply and remove from large burns than is the residue > of a cream. Sometimes a low voltage DC current is > applied across a sheet to accelerate release of Ag+ > from the cloth. (4,7) Additional clinical uses include > aseptic coverings for plastic surgery, traumatic > wounds, leg ulcers, skin grafts, incisions, abrasions > and minor cuts. Plastic indwelling catheters coated > with silver compounds8 are being developed to retard > the formation of biofilms and stem the incidence of > nosocomial infection. The use of Ag-coated nylon > threads in electroretinograms has allowed the > detection of tissue damage without fear of infection. > (9) Silver salts have traditionally been administered > to the eyes of newborn infants to prevent neonatal eye > infections. Dental amalgam, so-called "silver > fillings," contain about 35% Ag (0) and 50% Hg (0), > but we do not know if sufficient Ag+ is released to > have an antimicrobial effect. It is known, however, > that the release of Hg2+ from dental amalgams selects > for metal-resistant bacteria. (10) > > Bacterial Resistance and Genetics > Bacterial resistance to silver sulfadiazine, with its > sometimes tragic consequences, has been periodically > reported. An Ag+-resistant Salmonella strain killed > three patients and required the closing of the burn > ward at Massachusetts General Hospital (MGH). (11) > Although silver sulfadiazine-resistant bacteria have > occasionally been observed in burn ward infections, > and while chromosomal mutations of clinical strains to > Ag+ resistance may also cause a problem in infection > (12), resistance rates have not been followed. > > The plasmid-determined gene cluster for silver > resistance from the MGH Salmonella (11) contained a > total of nine genes, seven of which we have named with > the two less recognized open reading frames still > called ORFs: in order silP (ORF105) silAB (ORF96) C > silRS silE. (1) The system encodes a periplasmic > Ag+-binding protein (SilE) plus two membrane Ag+ > efflux pumps (SilCBA and SilP). The central six genes > (silA through silS) produce products that are > homologous to an unstudied gene cluster on the > Escherichia coli genome (currently called ybdE, ylcD, > ylcC, ylcB, ylcA and ybcZ, in order) and less closely > to other metal resistance systems. In Southern > blotting DNA/DNA hybridization analysis of clinical > isolates with homologous DNA, the central six genes > appear to always be present together, but homologs of > the outer two genes, silP and silE, are occasionally > missing (A. Gupta et al., in prep.). The six genes, > silPORF105ABORF96silC, are co-transcribed in a very > long mRNA. (1) The regulatory gene pair silRS is > co-transcribed separately, and silE is transcribed by > itself as a third mRNA. (1) > > Mechanism of Resistance > The functions of silver-resistance gene products can > be recognized by homology to other gene products that > have been studied. SilP is a membrane P-type ATPase > that pumps Ag+ from the cell1, (13,14) and is most > similar to Cu+ and Cd2+ efflux ATPases. SilCBA > (probably together with the ORF96 product) form a > second Ag+ efflux pump driven by the membrane > potential and not ATP. This pump consists of three > proteins, one in the inner membrane (SilA), another in > the outer membrane (SilC), and the third bridging the > periplasmic space (SilB). Three-protein membrane > potential-driven cation/proton exchangers were > initially recognized in our laboratory with a > bacterial Cd2+/Zn2+/Co2+ system. (14) > > This silver resistance system is the first time we > have seen three different mechanisms in a single toxic > metal cation resistance determinant. It appears to be > transcriptionally controlled by the products of two > genes, SilS (a histidine-containing membrane > auto-kinase "sensor") and SilR (a cytoplasmic > DNA-binding activator "responder" that contains an > aspartate residue that is trans-phosphorylated from > SilS). SilRS is homologous in sequence to members of > the large family of two-component sensor/responder > transcriptional regulators that respond to > extracellular signals. (1,14) > > SilE is a small periplasmic Ag+-binding protein that > binds Ag+ ions specifically at the cell surface, > presenting the first line of resistance against Ag+ > toxicity. The SilE protein has been purified to > homogeneity and extensively studied by J-F Lo et al. > (in prep.). The SilE protein contains ten histidine > residues that bind five Ag+ cations1 (J-F Lo et al., > in prep.). In contrast to other metal-binding > proteins, SilE has no cysteine residues. Binding of > Ag+ to the SilE protein brings about an unusually > large change in protein folding, from essentially > disordered, to a predominantly alpha helical > structure. At this early stage, we do not know whether > silE, which confers some Ag+ resistance by itself, > will ever be found alone or how the various sil gene > products interact for full resistance. > > Non-Clinical Uses of Silver > Our primary concern remains Ag+ usage in the clinic > and the selection for Ag+ resistance. The wide spread, > often unchecked application of silver products as > biocides is adding to the problem. Silver-containing > products are used in hospital and hotel water > distribution systems to control infectious agents > (e.g., Legionella). Silver has been used to sterilize > recycled water aboard the MIR space station and on the > NASA space shuttle. (15) Home-water purification units > sold in the US supermarkets contain silverized > activated carbon filters and ion-exchange resins. > Silver is a health additive in traditional Chinese and > Indian Ayurvedic medicine. (16) In Mexico, > supermarkets sell Microdyn, colloidal silver in > gelatin, to disinfect salad vegetables and drinking > water. Johnson Matthey Chemicals (UK) uses an > inorganic composite with immobilized slow-release > silver as a preservative in cosmetics and toiletries. > (17) In Japan, a new compound is mixed into plastics > for lasting antimicrobial protection of telephone > receivers, calculators, toilet seats, and children's > toys. (18) Metallic silver-copper containing ceramic > disks, marketed as "Clean Power Plus," are sold as an > alternative to laundry detergents. (19) Silver > addition to fabrics (similar to clinical use of > Ag-nylon) is proposed to reduce buildup of microbial > populations and therefore offensive smells in camping > gear and clothing. While folk remedies and "snake oil" > preparations are not the same, they are coupled here > as representative of applications with suspect > benefit. (9) Over-the-counter Ag+ health food > supplements are probably not effective (20) and are > frequently mislabeled. (21) The non-clinical uses of > silver appear endless, with one possible, detrimental > side-effect being the lessening of its usefulness as > an antimicrobial agent. > > What is Needed > The identification of the genes for silver resistance, > and the determination of closely related genes in > bacteria from environmental and clinical environments, > and from diverse geographical locations (A. Gupta et > al., in prep.) should eliminate recent skepticism > about the existence of silver-resistant bacteria. Now > that the means for identifying silver resistance > determinants in Enterobacteriaceae is available, > similar efforts should be made with respect to other > common pathogens, particularly those associated with > large burns (i.e., pseudomonads and staphylococci). > The wide and rather uncontrolled use of silver > products may result in increased resistance, analogous > to the emergence of antibiotic- and other > biocide-resistant bacteria. Undermining the benefits > of these compounds would be unfortunate to the > clinical and hygienic uses that depend on the > microcidal properties of silver. > > References > 1. Gupta A, Matsui K, Lo JF, Silver S. 1999. Nature > Medicine 5:183-188. > 2. Gupta A, Maynes M, Silver S. 1998. Applied > Environmental Microbiol 64: 5042-5045. > 3. Rosenkranz HS, Carr HS. 1972. Antimicrob Agents > Chemother 2: 367-372; > 4. Monafo WW, West MA. 1990. Drugs 40:364-373; Fox CL > Jr, Rao TN, Azmeth R, Gandhi SS, Modak S. 1990. J Burn > Care > Rehabilitation 11:112-117. > 5. Deitch EA, Marino AA, Malakanok V, Albright JA. > 1987. J Trauma 27: 301-304. > 6. Adams, AP, Santschi EM, Mellencamp MA. 1999. > Veterinary Surgery 28: 219-225. > 7. Miller L, Hansbrough J, Slater H, Goldfarb IW , > Kealey P, Saffle J, Kravitz M, Silverstein P. 1990. J > Burn Care Rehabilitation > 11:35-41. > 8. Modak S, Fox P, Stanford J, Sampath L, Fox CL Jr. > 1986. J Burn Care Rehabilitation 7: 422-425. > 9. Gabriel MM, Mayo MS, May LL,Simmons RB, Ahearn DG. > 1996. Current Microbiol 33:1-5. The Silver Institute. > Washington, > DC, USA. > 10. Lorscheider FL, Vimy MJ, Summers AO. 1995. FASEB J > 9:504-508, 1499-1500. > 11 McHugh SL, Moellering RC, Hopkins CC, Swartz MN. > 1975. Lancet i: 235-240. > 12. Li XZ, Nikaido H, Williams KE. 1997. J Bacteriol > 179:6127-6132. > 13. Silver S, Gupta A, Matsui K, Lo J-F. 1999. > Metal-Based Drugs 6 (in press). > 14. Silver S, Phung LT. 1996 Annual Review Microbiol > 50: 753-789. > 15. Adachi K (editor). Colloidal Silver. > Educate-Yourself. Costa Mesa, CA, USA. > 16. Reach for Life Enterprises. Fresno, CA, USA. > 17. Johnson Matthey. London, England, UK. > 18. Amenitop, silica gel microspheres containing a > silver-thiosulfate complex. Washington Post, February > 5, 1993. > 19. Mass Appeal Marketing. Torrance, CA, USA. > 20. Fung MC, Weintraub M, Bowen DL. 1995. JAMA > 274:1196-1197. > 21. US Food and Drug Administration. 1996. > Over-the-counter drug products containing colloidal > silver ingredients or silver salts. Federal Register, > October 15, 61(200): 53685-53688; US Food and Drug > Administration. 1994. FDA Health Fraud Bulletin #19, > Colloidal Silver, October 7. > > http://www.healthsci.tufts.edu/apua/Newsletter > > _______________________________________________________ > Do You Yahoo!? > Get your free @yahoo.ca address at http://mail.yahoo.ca > > -- > The silver-list is a moderated forum for discussion of colloidal silver. > > To join or quit silver-list or silver-digest send an e-mail message to: > [email protected] -or- [email protected] > with the word subscribe or unsubscribe in the SUBJECT line. > > To post, address your message to: [email protected] > Silver-list archive: http://escribe.com/health/thesilverlist/index.html > List maintainer: Mike Devour <[email protected]>
