Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

Harbut, Michael B.; Vilchèze, Catherine; Luo, Xiaozhou; Hensler, Mary E.; Guo, Hui; Yang, Baiyuan; Chatterjee, Arnab K.; Nizet, Victor; Jacobs, William R.; Schultz, Peter G.; Wang, Feng

doi:10.1073/pnas.1504022112

Cited by 268 publications

(350 citation statements)

References 52 publications

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“…Another drug, auranofin, has recently been reported to have strong antimicrobial activity against several Gram-positive organisms (15)(16)(17), and our results agree well with these reports, as the IC 50 of auranofin was well below the lowest concentration tested (0.6 M).…”

Section: Resultssupporting

confidence: 92%

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Torres

Abercrombie

Srinivasan

et al. 2016

Antimicrob Agents Chemother

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It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 M, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus. We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.

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Section: Resultssupporting

confidence: 92%

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Torres

Abercrombie

Srinivasan

et al. 2016

Antimicrob Agents Chemother

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“…This is becoming increasingly important as the potential indications for auranofin continue to expand. Besides the potential of auranofin as a broadly active antiparasitic and chemotherapeutic agent, a recent publication also demonstrated its efficacy against drug-resistant Gram-positive bacteria, including Mycobacteria tuberculosis (22). Thus, auranofin has the potential to be an important repurposed drug.…”

Section: Discussionmentioning

confidence: 99%

Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent

Capparelli

Bricker-Ford

Rogers

et al. 2017

Antimicrob Agents Chemother

114

113

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Under an NIH priority to identify new drugs to treat class B parasitic agents, we performed high-throughput screens, which identified the activity of auranofin (Ridaura) against Entamoeba histolytica and Giardia intestinalis, major causes of water-and foodborne outbreaks. Auranofin, an orally administered, gold (Au)-containing compound that was approved by the FDA in 1985 for treatment of rheumatoid arthritis, was effective in vitro and in vivo against E. histolytica and both metronidazole-sensitive and -resistant strains of Giardia. We now report the results of an NIH-sponsored phase I trial to characterize the pharmacokinetics (PK) and safety of auranofin in healthy volunteers using modern techniques to measure gold levels. Subjects received orally 6 mg (p.o.) of auranofin daily, the recommended dose for rheumatoid arthritis, for 7 days and were followed for 126 days. Treatment-associated adverse events were reported by 47% of the subjects, but all were mild and resolved without treatment. The mean gold maximum concentration in plasma (C max ) at day 7 was 0.312 g/ml and the half-life (t 1/2 ) 35 days, so steadystate blood levels would not be reached in short-term therapy. The highest concentration of gold, 13 M (auranofin equivalent), or more than 25ϫ the 50% inhibitory concentration (IC 50 ) for E. histolytica and 4ϫ that for Giardia, was in feces at 7 days. Modeling of higher doses (9 and 21 mg/day) was performed for systemic parasitic infections, and plasma gold levels of 0.4 to 1.0 g/ml were reached after 14 days of treatment at 21 mg/day. This phase I trial supports the idea of the safety of auranofin and provides important PK data to support its potential use as a broadspectrum antiparasitic drug. (This study has been registered at ClinicalTrials.gov under identifier NCT02089048.)

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“…Auranofin is a FDA approved anti-rheumatic drug found to be effective against Entamoeba histolytica, Mycobacterium tuberculosis, and many Gram-positive pathogens (44,45). To unveil the mechanism of action of auranofin in Leishmania, its sensitivity was assessed in both WT and SepSecS null mutants.…”

Section: Discussionmentioning

confidence: 99%

Leishmania donovani Encodes a Functional Selenocysteinyl-tRNA Synthase

Manhas¹,

Gowri²,

Madhubala

2016

Journal of Biological Chemistry

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The synthesis of selenocysteine, the 21st amino acid, occurs on its transfer RNA (tRNA), tRNA Sec . tRNA Sec is initially aminoacylated with serine by seryl-tRNA synthetase and the resulting seryl moiety is converted to phosphoserine by O-phosphoseryl-tRNA kinase (PSTK) in eukaryotes. The selenium donor, selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase. Selenocysteinyl-tRNA synthase (SepSecS) then uses the O-phosphoseryl-tRNA Sec and selenophosphate to form Sec-tRNA Sec in eukaryotes. Here, we report the characterization of selenocysteinyl-tRNA synthase from Leishmania donovani. Kinetoplastid SepSecS enzymes are phylogenetically closer to worm SepSecS. LdSepSecS was found to exist as a tetramer. Leishmania SepSecS enzyme was found to be active and able to complement the ⌬selA deletion in Escherichia coli JS1 strain only in the presence of archaeal PSTK, indicating the conserved nature of the PSTK-SepSecS pathway. LdSepSecS was found to localize in the cytoplasm of the parasite. Gene deletion studies indicate that Leishmania SepSecS is dispensable for the parasite survival. The parasite was found to encode three selenoproteins, which were only expressed in the presence of SepSecS. Selenoproteins of L. donovani are not required for the growth of the promastigotes. Auranofin, a known inhibitor of selenoprotein synthesis showed the same sensitivity toward the wild-type and null mutants suggesting its effect is not through binding to selenoproteins. The three-dimensional structural comparison indicates that human and Leishmania homologs are structurally highly similar but their association modes leading to tetramerization seem different.

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Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

Cited by 268 publications

References 52 publications

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent

Leishmania donovani Encodes a Functional Selenocysteinyl-tRNA Synthase

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