Repurposing auranofin as an intestinal decolonizing agent for vancomycin-resistant enterococci

2020

Sci Rep

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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.

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confidence: 99%

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

Elkashif

2020

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“…Auranofin is an FDA-approved anti-rheumatoid arthritis drug, with a well-studied safety profile for human use 16,17 . Recently, auranofin has gained interest in repurposing for treatment of bacterial and parasitic infections [18][19][20][21][22][23] .…”

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confidence: 99%

“…Furthermore, it is undergoing Phase II clinical trials for the treatment of amoebic dysentery, giardiasis (NCT02736968) and tuberculosis (NCT02968927). Auranofin possesses strong antibacterial and antifungal activities 17,[22][23][24][25] . We previously demonstrated that auranofin has a potent anticlostridial activity with strong inhibition of both toxins and spores production in vitro 24 .…”

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confidence: 99%

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Abutaleb

2020

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Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin's in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti-C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI. Clostridioides difficile is the worldwide leading cause of nosocomial infections and antibiotic-associated diarrhea 1. A recent report released by the Centers for Disease Control and Prevention (CDC) stated that about 223,900 patients were hospitalized with C. difficile infections (CDI) in the United States in 2017, which was associated with around 12,800 mortality cases and in excess of $1 billion healthcare cost 2. CDI symptoms range from mild to severe watery diarrhea to more severe life threatening complications such as pseudomembranous colitis, toxic megacolon, colon perforation, sepsis, systemic inflammatory response syndrome and shock 3. Disease manifestations are attributed to the toxin-mediated damage elicited by the two major toxins TcdA and TcdB. These toxins catalyze inactivation of host GTPases (Rac, Rho and CDC42) and perturbation of actin cytoskeleton, ultimately causing intense inflammation, loss of tight junctions of the intestinal mucosal layer, enormous fluid secretion, cell rounding and finally necrosis and apoptosis of the colonic mucosal cells 4,5. The incidence and severity of CDI has increased dramatically due to the overuse of antibiotics and the emergence of hypervirulent epidemic strains such as, but not limited to, pulsed-field gel type North American pulsotype 1 (NAP1) or PCR ribotype 027, which were responsible for several outbreaks globally 6,7. Moreover, the clinical management of CDI is hindered by the ability of C. difficile to produce spores which are highly resistant to environmental conditions, antibiotics and disinfection processes. Spores can persist on unsuitable environments for long periods and spread in the e...

“…Drug repositioning is a promising field that investigates new therapeutic opportunities for existing approved drugs with readily available information on their pharmacokinetic profile, dosages, and toxicity to humans (14)(15)(16)(17)(18)(19). This approach can significantly reduce the total cost, time, and effort to develop novel antibacterial agents.…”

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confidence: 99%

Repurposing Salicylamide for Combating Multidrug-Resistant Neisseria gonorrhoeae

Alhashimi

Mayhoub

Antimicrob Agents Chemother

2019

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The U.S. Centers for Disease Control and Prevention (CDC) lists Neisseria gonorrhoeae as one of the most urgent antibiotic-resistant threats in the United States. This is due to the emergence of clinical isolates that have developed resistance to nearly every antibiotic used to treat gonorrhea and highlights the critical need to find new therapeutics. The present study discovered salicylamide, an analgesic and antipyretic drug, has antibacterial activity against 40 different antibiotic-resistant strains of N. gonorrhoeae (MIC, 8 to 32 μg/ml) with low frequency of resistance <2.4 × 10−9. Interestingly, salicylamide did not inhibit growth of bacterial species in the vaginal microflora involved in defense against gonococcal infections, such as Lactobacillus gasseri, Lactobacillus jensenii, Lactobacillus johnsonii, and Lactobacillus crispatus. A time-kill assay revealed that salicylamide is a rapidly bactericidal drug, as it eradicated a high inoculum of N. gonorrhoeae within 10 h. Salicylamide was superior to the drug of choice, ceftriaxone, in reducing the burden of intracellular N. gonorrhoeae by 97% in infected endocervical cells. Furthermore, salicylamide outperformed ceftriaxone in reducing expression of the proinflammatory cytokine interleukin 8 (IL-8) from endocervical cells infected with N. gonorrhoeae. A checkerboard assay revealed that salicylamide exhibited a synergistic interaction with tetracycline and additive relationships with azithromycin, ciprofloxacin, and ceftriaxone. A more in-depth investigation of the structure-activity relationship of derivatives of salicylamide revealed the amide and hydroxyl groups are important for antigonorrheal activity. In conclusion, this study identified salicylamide as a promising candidate for further investigation as a novel treatment option for multidrug-resistant gonorrhea.