Repurposing auranofin for the treatment of cutaneous staphylococcal infections

Abstract

The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625 μg/mL to 0.125 μg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections.

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

“…The traditional route of antifungal innovation and regulatory approval is a time-consuming, expensive venture. This has led researchers to explore alternative approaches, such as drug repurposing, to expedite anti-infective drug development [27,31,55–58]. …”

Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

“…Independent of its antirheumatic effect, several studies have reported the anti-infective properties of this drug against important parasitic and bacterial pathogens including Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, Entamoeba histolytica, Staphylococcus aureus , and Streptococcus pneumoniae (Jackson-Rosario et al, 2009; Debnath et al, 2012; Cassetta et al, 2014; Harbut et al, 2015; Thangamani et al, 2016a,b). However, a dichotomy exists regarding the antimicrobial MOA of auranofin.…”

“…For example, several reports have demonstrated that auranofin, an orally bioavailable FDA-approved drug for treatment of rheumatoid arthritis, exhibits potent antibacterial and antiparasitic activities (Jackson-Rosario et al, 2009; Debnath et al, 2012; Cassetta et al, 2014; Hokai et al, 2014; Aguinagalde et al, 2015; Thangamani et al, 2016a,b). This discovery led to the FDA granting auranofin Orphan Drug status for treatment of amebiasis.…”

The FDA- approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells

“…Recently, auranofin was approved by FDA for phase II clinical trials for cancer therapy. The mechanism of action of auranofin involves the inhibition of redox enzymes such as thioredoxin reductase, induction of endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR) (2)(3)(4)(5). Inhibition of these redox enzymes leads to cellular oxidative stress and intrinsic apoptosis (6,7).…”