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Abstract
Multidrug‐resistant (MDR) Gram‐negative bacteria account for a majority of fatal infections, and development of new antibiotic principles and drugs is therefore of outstanding importance. Here, we report that five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells. The silver and ebselen combination causes a rapid depletion of glutathione and inhibition of the thioredoxin system in bacteria. Silver ions were identified as strong inhibitors of Escherichia coli thioredoxin and thioredoxin reductase, which are required for ribonucleotide reductase and DNA synthesis and defense against oxidative stress. The bactericidal efficacy of silver and ebselen was further verified in the treatment of mild and acute MDR E. coli peritonitis in mice. These results demonstrate that thiol‐dependent redox systems in bacteria can be targeted in the design of new antibacterial drugs. The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems and might be developed for novel efficient treatments against MDR Gram‐negative bacterial infections.
Highlights
The spread of multidrug-resistant (MDR) bacteria threatens modern medical treatment for infectious diseases (Walsh, 2003; Lewis, 2013)
The toxicity of ebselen itself (2, 4, 8 lM) on bacterial and mammalian cells was similar (Fig 1A and B) with no effects on bacterial growth (Fig EV1). These results indicate that treatment of Ag+ with ebselen in combination exhibits significant selective synergistic toxicity on bacteria over mammalian cells, and the dramatic decrease in minimum inhibitory concentration (MIC) of silver against bacteria in the presence of ebselen make the systemic medical use of silver feasible
A, B E. coli DHB4 grown to OD600 nm of 0.4 were treated with 20 lM ebselen and 5 lM AgNO3, and FACS histograms (A) and mean MFI Æ standard deviation (SD) (B) of H2DCF-DA-stained E. coli were detected
Summary
The spread of multidrug-resistant (MDR) bacteria threatens modern medical treatment for infectious diseases (Walsh, 2003; Lewis, 2013). There are two major thiol-dependent enzyme systems in prokaryotic and eukaryotic cells based on thioredoxin (Trx) and glutathione (GSH), which transfer electrons from NADPH to their substrates via thioredoxin reductases (TrxR) and glutathione reductases (GR) (Holmgren, 1989; Ritz & Beckwith, 2001; Lillig & Holmgren, 2007) These two systems are critical for DNA synthesis, defense against oxidative stress, repair of oxidized proteins, and post-translational modifications such as protein S-glutathionylation, or S-nitrosylation, which are important for many cellular processes (Holmgren, 1989; Ritz & Beckwith, 2001; Lillig & Holmgren, 2007)
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