Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae

Abstract

Neisseria gonorrhoeae represents an urgent public health threat due to the rapid emergence of resistance to current antibiotics and the limited number of anti-gonococcal agents currently in clinical trials. This study utilized a drug repositioning strategy to investigate FDA-approved gold-containing drugs against N. gonorrhoeae. Auranofin, sodium aurothiomalate and aurothioglucose inhibited 48 clinical isolates of N. gonorrhoeae including multidrug-resistant strains at a concentration as low as 0.03 µg/mL. A time-kill assay revealed that auranofin exhibited rapid bactericidal activity against N. gonorrhoeae. Moreover, both sodium aurothiomalate and aurothioglucose did not inhibit growth of vaginal protective commensal lactobacilli. Auranofin, in combination with azithromycin, ceftriaxone, cefixime or tetracycline showed an additive effect against four N. gonorrhoeae strains, suggesting the possibility of using auranofin in dual therapy. Moreover, auranofin reduced the burden of intracellular N. gonorrhoeae by over 99% outperforming the drug of choice ceftriaxone. Auranofin was found superior to ceftriaxone in reducing the secretion of the pro-inflammatory cytokine IL-8 by endocervical cells infected with N. gonorrhoeae. Furthermore, auranofin exhibited a prolonged post-antibiotic effect over 10 h, as well as inability to generate resistant mutants. Overall, the current study suggests that repurposing gold-containing drugs, like auranofin, for treatment of gonorrhea warrants further investigation.

Repurposing of auranofin and honokiol as antifungals against Scedosporium species and the related fungus Lomentospora prolificans

“…Combining old drugs with front-line medication is common, but such studies are still limited regarding ARF and HOK. Additive interactions, but rarely synergistic, were reported when combining ARF with antibiotics against pathogenic bacteria [20,21,68,69]. Similar findings were reported when combining ARF with fluconazole or amphotericin B against pathogenic yeasts [23,25], which is consistent with the few additive interactions observed for the combination of ARF with VRC.…”

“…Auranofin inhibits the HMW-TrxR via irreversible binding to its selenocysteinyl residue [16], but its inhibitory activity was also reported against LMW-TrxR lacking selenocysteine [17,18]. Therefore, it has been proposed for many infectious diseases, including bacterial, parasitic, and fungal infections [19][20][21][22][23][24]. In fungi, ARF demonstrated promising in vitro activity against several Candida species or Cryptococcus (Cr.)…”

Epidemiology, Treatments, and Vaccine Development for Antimicrobial-Resistant Neisseria gonorrhoeae: Current Strategies and Future Directions

“…Of note, other drugs used for treatments outside of antimicrobials also warrant investigation. For example, Auranofin, a gold-containing drug used for rheumatoid arthritis, was shown to outperform ceftriaxone in reducing burden of intracellular N. gonorrhoeae (99%), reducing secretion of IL-8 secretion, having prolonged post-antibiotic effects, and lacking an ability to generate resistant mutants [ 84 ]. Another example is with carbamazepine and methyldopa, an anti-epileptic and anti-hypertensive drug.…”

Investigating auranofin for the treatment of infected diabetic pressure ulcers in mice and dermal toxicity in pigs

“…Auranofin was originally approved as a second-line oral drug for treatment of rheumatoid arthritis. More recently, auranofin has received interest in being repurposed as an antibacterial agent 33 – 36 . We suspected auranofin would be a promising topical agent to treat diabetic pressure ulcers infected with MRSA as auranofin possesses potent antibacterial and antibiofilm activity in vitro and in vivo; additionally, auranofin reduced expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) associated with impaired wound healing in uncomplicated cutaneous abscesses in mice 16 , 20 .…”