Abstract
There is a drought of new antibacterial compounds that exploit novel targets. Thioredoxin reductase (TrxR) from the Gram-positive bacterial antioxidant thioredoxin system has emerged from multiple screening efforts as a potential target for auranofin, ebselen, shikonin, and allicin. Auranofin serves as the most encouraging proof of concept drug, demonstrating TrxR inhibition can result in bactericidal effects and inhibit Gram-positive bacteria in both planktonic and biofilm states. Minimal inhibitory concentrations are on par or lower than gold standard medications, even among drug resistant isolates. Importantly, existing drug resistance mechanisms that challenge treatment of infections like Staphylococcus aureus do not confer resistance to TrxR targeting compounds. The observed inhibition by multiple compounds and inability to generate a bacterial genetic mutant demonstrate TrxR appears to play an essential role in Gram-positive bacteria. These findings suggest TrxR can be exploited further for drug development. Examining the interaction between TrxR and these proof of concept compounds illustrates that compounds representing a new antimicrobial class can be developed to directly interact and inhibit the validated target.
Highlights
Years of antibiotic misuse and over prescription has taken a toll on the current drug arsenal, resulting in the emergence and expansion of drug resistant microbes
We explore auranofin, shikonin, ebselen, and allicin as compounds that inhibit Thioredoxin reductase (TrxR) and remark on the antimicrobial activity profiles
Angelucci et al (2009) present alternative findings in the parasite Schistosoma mansoni where a glutaredoxin domain is fused with a TrxR domain to create thioredoxin-glutathione reductase. It is indicated by the data of this study, that auranofin interacts with thioredoxin-glutathione reductase through a selenocysteine mediated transfer of gold from auranofin to Cys sites and gold provides the inhibitory activity, essentially making auranofin the pro-drug for gold delivery (Angelucci et al, 2009). It is not yet be fully elucidated how auranofin interaction with TrxR in Gram-positive bacteria leads to inhibition but there is the potential that the CXXC motif could be a target
Summary
Years of antibiotic misuse and over prescription has taken a toll on the current drug arsenal, resulting in the emergence and expansion of drug resistant microbes. We explore auranofin, shikonin, ebselen, and allicin as compounds that inhibit TrxR and remark on the antimicrobial activity profiles. It is not yet be fully elucidated how auranofin interaction with TrxR in Gram-positive bacteria leads to inhibition but there is the potential that the CXXC motif could be a target.
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