Thioredoxin Reductase Is a Valid Target for Antimicrobial Therapeutic Development Against Gram-Positive Bacteria

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.

A Fluorescent Probe to Detect Quick Disulfide Reductase Activity in Bacteria

“…Interestingly, there was little difference in total thiol levels between Gram-negative and -positive strains ( Figure 3 b). Though Gram-positive bacteria S. aureus and B. cereus contained only Trx system [ 5 , 19 , 42 , 43 ], they had 10-fold higher disulfide reducibility compared to Gram-negative bacteria E. coli which was equipped with both Trx and GSH-Grx systems, indicating that a very active Trx system was present in these bacteria.…”

Gold-Derived Molecules as New Antimicrobial Agents

“…As the TrxR system is essential for the antioxidant system of Gram-positive bacteria, this result is in accordance with the particularly high activity observed against Gram-positive strains. TrxR was also hypothesized as one of the multiple bacterial targets of complex 1 ( Thangamani et al, 2016 ), confirming the interest in bacterial Trx and TrxR as viable antibacterial drug targets for gold-based anti-infective agents ( Felix et al, 2021 ).…”

Understanding the Role of the Antioxidant Drug Erdosteine and Its Active Metabolite on Staphylococcus aureus Methicillin Resistant Biofilm Formation

“…Accordingly, proteins of which the transcription is usually induced by oxidative stress, such as aldehyde dehydrogenase, alkyl hydroperoxide reductase C or thioredoxin, were found downregulated in the treated samples [ 43 , 44 , 45 ]. Thioredoxin is present in all living cells, including bacteria and fungi, and it acts as an antioxidant system through the conversion of thiol and disulfide bonds [ 46 ]. It is a cytoplasmatic protein but it is secreted extracellularly in the matrix in many bacterial biofilms, including S. aureus , under infections [ 47 ].…”