Antibacterial and antivirulence activities of auranofin against Clostridium difficile

AbdelKhalek, Ahmed; Abutaleb, Nader S.; Mohammad, Haroon; Seleem, Mohamed N.

doi:10.1016/j.ijantimicag.2018.09.018

Cited by 61 publications

(62 citation statements)

References 38 publications

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“…Investigation into the mechanisms of AXPN revealed that drug administration was associated with increased neutrophil recruitment that contributed to an elevated IL-33 response, which was critical for pathogen control. Our findings paralleled recent observations that several FDAapproved drugs, including auranofin, an antirheumatic, and mistroprostol, a prostaglandin analog, were effective against experimental CDI (39)(40)(41). However, important differences in the modes of action exist between these drugs.…”

Section: Discussionsupporting

confidence: 88%

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

Andersson

Peniche

Galindo

et al. 2020

mBio

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Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils. IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

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Section: Discussionsupporting

confidence: 88%

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

Andersson

Peniche

Galindo

et al. 2020

mBio

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“…Auranofin is an FDA-approved, gold-containing, drug used to treat rheumatoid arthritis. Previous studies on auranofin have reported that the drug possesses potent antibacterial activity against clinically-pertinent pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridioides difficile [15][16][17][18][19][20] . However, no reports have investigated the effect of auranofin against N. gonorrhoeae.…”

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confidence: 99%

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

Elkashif

Seleem

2020

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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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“…toxin inhibition assay. Based on their proposed mechanism of action, mithramycin A 56 and aureomycin 57 , were investigated to evaluate their effects on toxin production by C. difficile ATCC BAA 1870, with slight modifications 58 . Briefly, C. difficile strain ATCC BAA 1870 was cultured on BHIS agar plates and incubated anaerobically for 48 hours at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Screening of Natural Products and Approved Oncology Drug Libraries for Activity against Clostridioides difficile

Pal

Seleem

2020

Sci Rep

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Clostridioides difficile is the most common cause of healthcare-associated diarrhea. infection of the gastrointestinal tract with this Gram-positive, obligate anaerobe can lead to potentially lifethreatening conditions in the antibiotic-treated populace. new therapeutics are urgently needed to treat this infection and prevent its recurrence. Here, we screened two libraries from the National Cancer Institute, namely, the natural product set III library (117 compounds) and the approved oncology drugs set V library (114 compounds), against C. difficile. In the two libraries screened, 17 compounds from the natural product set III library and 7 compounds from the approved oncology drugs set V library were found to exhibit anticlostridial activity. The most potent FDA-approved drugs (mitomycin C and mithramycin A) and a promising natural product (aureomycin) were further screened against 20 clinical isolates of C. difficile. The anticancer drugs, mitomycin C (MIC 50 = 0.25 μg/ml) and mithramycin A (MIC 50 = 0.015 μg/ml), and the naturally derived tetracycline derivative, aureomycin (MIC 50 = 0.06 μg/ ml), exhibited potent activity against C. difficile strains. Mithramycin A and aureomycin were further found to inhibit toxin production by this pathogen. Given their efficacy, these compounds can provide a quick supplement to current treatment to address the unmet needs in treating C. difficile infection and preventing its recurrence.Clostridioides difficile is the leading cause of health care-associated diarrhea and mortality in the United States 1-4 . The Centers for Disease Control and Prevention (CDC) classified C. difficile as an urgent threat due to the immense suffering and death of thousands of patients each year. As per the 2017 estimates, the bacterium accounted for 223,900 cases with 12, 800 deaths and an attributable health care cost of $ 1 billion 5 . The characteristic manifestation of C. difficile-associated diarrhea (CDAD) ranges from mild diarrhea to pseudomembranous colitis, and toxic megacolon, and 1 out of every 11 patients aged 65 years or older dies within 30 days of diagnosis 6 .Antibiotic therapy remains a pivotal risk factor, as it aids the growth of C. difficile in the colon 7 . In its unperturbed state, the indigenous microflora of the colon serve as a host defense mechanism by providing resistance against colonization of the pathogen 8 . The use of antibiotics disrupts the host microflora, rendering individuals susceptible to C. difficile infection (CDI). In the absence of these gut microflora, following oral ingestion, the dormant C. difficile spores germinate, colonize the vacant nutrient niche in the gut, and release the enterotoxin TcdA and the cytotoxin TcdB 9,10 . These toxins A and B constitute the major virulence factors of the pathogen that damage the colonic epithelium triggering inflammatory responses that cause the range of symptoms associated with CDI 10,11 . Paradoxically, the standard treatment options for CDI includes oral administration of the antibiotics vancomycin or fidaxomi...

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Antibacterial and antivirulence activities of auranofin against Clostridium difficile

Cited by 61 publications

References 38 publications

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

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

Screening of Natural Products and Approved Oncology Drug Libraries for Activity against Clostridioides difficile

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