Abstract
Silver is widely used for its antimicrobial properties, but microbial resistance to heavy metals is increasing. Silver(II) compounds are more oxidizing and therefore have the potential to overcome resistance via extensive attack on cellular components, but have traditionally been hard to stabilize for biological applications. Here, the high oxidation state cation was stabilised using pyridinecarboxylate ligands, of which the 2,6-dicarboxypyridine Ag(II) complex (Ag2,6P) was found to have the best tractability. This complex was found to be more stable in phosphate buffer than DMSO, allowing studies of its interaction with water soluble antioxidants and biological macromolecules, with the aim of demonstrating its potential to oxidize them, as well as determining the reaction products. Spectrophotometric analysis showed that Ag2,6P was rapidly reduced by the antioxidants glutathione, ascorbic acid and vitamin E; the unsaturated lipids arachidonic and linoleic acids, model carbohydrate β-cyclodextrin, and protein cytochrome c also reacted readily. Analysis of the reaction with glutathione by NMR and electrospray mass spectrometry confirmed that the glutathione was oxidized to the disulfide form. Mass spectrometry also clearly showed the addition of multiple oxygen atoms to the unsaturated fatty acids, suggesting a radical mechanism, and cross-linking of linoleic acid was observed. The seven hydroxyl groups of β-cyclodextrin were found to be completely oxidized to the corresponding carboxylates. Treatment of cytochrome c with Ag2,6P led to protein aggregation and fragmentation, and dose-dependent oxidative damage was demonstrated by oxyblotting. Thus Ag2,6P was found to be highly oxidizing to a wide variety of polar and nonpolar biological molecules.
Highlights
The antiseptic and oligodynamic behaviour of silver has been appreciated for more than 200 years (Marx and Barillo 2014; Mijnendonckx et al 2013)
Even in recent years its application as a biocide has been limited to the use of a few relatively simple preparations (Azocar et al 2014)
Ag2,6P was observed to be reasonably soluble in both water (* 10 mM) and DMSO (* 20 mM)
Summary
The antiseptic and oligodynamic behaviour of silver has been appreciated for more than 200 years (Marx and Barillo 2014; Mijnendonckx et al 2013). Even in recent years its application as a biocide has been limited to the use of a few relatively simple preparations (Azocar et al 2014). Many medical items such as catheters and prostheses are coated with the elemental form of silver, which prevents colonization of their surface by pathogens (Hetrick and Schoenfisch 2006). Since the late 1960s, silver sulfadiazine (SSD, or FlamazineÒ) has been common in anti-bacterial preparations for the treatment of burns (Atiyeh et al 2007) Even this compound is a simple preparation comprising an antimicrobial cation and anion formulated together as a weakly bonded complex (Cook and Turner 1975). There has been robust interest in developing new silver-based anti-infective agents such as silver nanoparticles (Ag/Ag2O), novel silver complexes and silver impregnated fabrics (Ag0/Ag?) (Fromm 2013; Konop et al 2016; Le Ouay and Stellacci 2015; Simoncic and Klemencic 2016; Singh et al 2015), these are mainly reformulations of silver in its commonest Ag0/Ag? forms
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