title: Silver coordination polymers for prevention of implant infection: thiol interaction, impact on respiratory chain enzymes, and hydroxyl radical induction.
abstract: Prosthetic joint replacements are used increasingly to alleviate pain and improve mobility of the progressively older and more obese population. Implant infection occurs in about 5% of patients and entails significant morbidity and high social costs. It is most often caused by staphylococci, which are introduced perioperatively. They are a source of prolonged seeding and difficult to treat due to antibiotic resistance; therefore, infection prevention by prosthesis coating with nonantibiotic-type anti-infective substances is indicated. A renewed interest in topically used silver has fostered development of silver nanoparticles, which, however, present a potential health hazard. Here we present new silver coordination polymer networks with tailored physical and chemical properties as nanostructured coatings on metallic implant substrates. These compounds exhibited strong biofilm sugar-independent bactericidal activity on in vitro-grown biofilms and prevented murine Staphylococcus epidermidis implant infection in vivo with slow release of silver ions and limited transient leukocyte cytotoxicity. Furthermore, we describe the biochemical and molecular mechanisms of silver ion action by gene screening and by targeting cell metabolism of S. epidermidis at different levels. We demonstrate that silver ions inactivate enzymes by binding sulfhydryl (thiol) groups in amino acids and promote the release of iron with subsequent hydroxyl radical formation by an indirect mechanism likely mediated by reactive oxygen species. This is the first report investigating the global metabolic effects of silver in the context of a therapeutic application. We anticipate that the compounds presented here open a new treatment field with a high medical impact.
authors.affiliation: Infection Biology, Department of Biomedicine, University Hospital, CH-4056 Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gordon
authors.forename: Tünde
authors.initials: T
authors.lastname: Vig Slenters
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Brunetto
authors.forename: Amer E
authors.initials: AE
authors.lastname: Villaruz
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Regine
authors.initials: R
authors.lastname: Landmann
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Fromm
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use*; D018441:Biofilms / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000627:therapeutic use*; D004579:Electron Transport; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism*; D020007:Implants, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use*; D012834:Silver / Q000737:chemistry / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000517:prevention & control*; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D020099:Coated Materials, Biocompatible; D011108:Polymers; D017665:Hydroxyl Radical; D012834:Silver