Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens

Abstract

Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections.

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

“…However, a recent crystallographic study conducted by Parsonage et al (2016) revealed that auranofin most likely does not bind to the cysteine residues in TrxR of E. histolytica . Another study, conducted by our research group, also demonstrated that TrxR is not the primary target of auranofin in bacteria (Thangamani et al, 2016a). We demonstrated that auranofin inhibits multiple biosynthetic pathways including DNA, protein and cell wall synthesis in bacteria (Thangamani et al, 2016a).…”

“…Another study, conducted by our research group, also demonstrated that TrxR is not the primary target of auranofin in bacteria (Thangamani et al, 2016a). We demonstrated that auranofin inhibits multiple biosynthetic pathways including DNA, protein and cell wall synthesis in bacteria (Thangamani et al, 2016a). However, the exact molecular target of auranofin, in bacteria, still remains unclear.…”

“…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.…”

Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci

“…Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter cloacae were obtained from the American Type Culture Collection (Manassas, VA, USA). Escherichia coli OP50, E. coli 1411 and E. coli ΔAcrAB were described before 41, 42 . The human colorectal cell line (HRT-18) was obtained from the American Type Culture Collection (Manassas, VA, USA).…”