Synergistic antibacterial effect of silver and ebselen against multidrug‐resistant Gram‐negative bacterial infections

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.

Characterization of synergistic antibacterial effect of silver nanoparticles and ebselen

“…The experiment was performed with the method previously described [21]. The dosage of AgNPs was adjusted to the same concentration of silver ion with reference [21], in detail, 0.54 lg/mL AgNPs is equal to 1 lM silver ion, and then 2-fold serial dilution.…”

“…The experiment was performed with the method previously described [21]. The dosage of AgNPs was adjusted to the same concentration of silver ion with reference [21], in detail, 0.54 lg/mL AgNPs is equal to 1 lM silver ion, and then 2-fold serial dilution. Pure recombinant 100 nM E.coli TrxR, in the presence of 200 lM NADPH, was incubated with a serial concentration of AgNPs which is equal to 1, 2, 3, 4, 5 lM silver ion in mass for 10 min, respectively, then the assay buffer containing 5 lM E. coli Trx and 2 mM DTNB was added and TrxR activities were detected with a DTNB reduction assay.…”

“…Given both AgNPs and ebselen have the inhibitory activities against bacterial TrxR [21][22][23][24], on the other hand, the similar level of IC 50 and MBC values of AgNPs for cells and bacteria, as well as their distinct response to ROS induced by AgNPs, we tried to combine with ebselen to decrease the dose of AgNPs on behalf of biosafety. The fractional inhibitory concentration (FIC) was measured with a standard method.…”

“…It was recently repurposed to be an antibacterial agent for killing MRSA and vancomycin-resistant S. aureus (VRSA) at a concentration of 20 lM [19,20]. Ebselen also displayed a synergistic antibacterial effect with silver ion against MDR Gramnegative bacteria [21]. The antibacterial mechanism of ebselen was the inhibition of bacterial thioredoxin reductase (TrxR) [22][23][24].…”

Effects of Programmed Local Delivery from a Micro/Nano‐Hierarchical Surface on Titanium Implant on Infection Clearance and Osteogenic Induction in an Infected Bone Defect

“…Ag + can decrease the enzymatic activity and cause the inhibition of oxidative respiratory chain, thus affecting metabolism and DNA replication of microorganisms . In addition, the oxidative stress with a large amount of active oxygen and reactive nitrogen intermediately provided by AgNPs could act against the bacteria . Long‐term antibacterial function added benefits to counter the possibility of bacterial infection from surrounding tissue as well as hematogenous sources of infection .…”