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

Abutaleb, Nader S.; Seleem, Mohamed N.

doi:10.1038/s41598-020-64882-9

Cited by 32 publications

(24 citation statements)

References 44 publications

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“…51 In Vivo Efficacy of HSGN-218 in a CDI Mouse Model. 52 The potent antibacterial activities of HSGN-218 against C. difficile prompted us to investigate its efficacy in a CDI mouse model and its potential to protect mice from CDI recurrence, as described before. As shown in Figure 4, vancomycin (10 mg/kg) protected 100% of mice up to five days, as previously reported.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo

Naclerio

Abutaleb

et al. 2020

J. Med. Chem.

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Clostridioides difficile is the leading cause of healthcare-associated infection in the U.S. and considered an urgent threat by the Centers for Disease Control and Prevention (CDC). Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved for the treatment of C. difficile infection (CDI), but these therapies still suffer from high treatment failure and recurrence. Therefore, new chemical entities to treat CDI are needed. Trifluoromethylthio-containing N-(1,3,4-oxadiazol-2-yl)benzamides displayed very potent activities [sub-μg/mL minimum inhibitory concentration (MIC) values] against Gram-positive bacteria. Here, we report remarkable antibacterial activity enhancement via halogen substitutions, which afforded new anti-C. difficile agents with ultrapotent activities [MICs as low as 0.003 μg/mL (0.007 μM)] that surpassed the activity of vancomycin against C. difficile clinical isolates. The most promising compound in the series, HSGN-218, is nontoxic to mammalian colon cells and is gut-restrictive. In addition, HSGN-218 protected mice from CDI recurrence. Not only does this work provide a potential clinical lead for the development of C. difficile therapeutics but also highlights dramatic drug potency enhancement via halogen substitution.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo

Naclerio

Abutaleb

et al. 2020

J. Med. Chem.

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“…[2,3] Auranofin is an FDA-approved drug previously used as an anti-inflammatory aid in the treatment of rheumatoid arthritis (Figure 1). It has since been tested for other diseases, showing antibacterial, [4][5][6][7][8][9][10][11] antifungal, [12][13][14] antiparasitic, [15,16] antiviral, [17][18][19][20][21] and antitumor [22] activities. The main mode of action (MOA) of auranofin has been suggested to be the inhibition of thioredoxin reductase (TrxR).…”

Section: Introductionmentioning

confidence: 99%

Gold Nanoclusters as Nanoantibiotic Auranofin Analogues

Ndugire

Raviranga

Lao

et al. 2021

Adv Healthcare Materials

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Auranofin, a gold(I)‐complex with tetraacetylated thioglucose (Ac4GlcSH) and triethylphosphine ligands, is an FDA‐approved drug used as an anti‐inflammatory aid in the treatment of rheumatoid arthritis. In repurposing auranofin for other diseases, it was found that the drug showed significant activity against Gram‐positive but was inactive against Gram‐negative bacteria. Herein, the design and synthesis of gold nanoclusters (AuNCs) based on the structural motif of auranofin are reported. Phosphine‐capped AuNCs are synthesized and glycosylated, yielding auranofin analogues with mixed triphenylphosphine monosulfonate (TPPMS)/Ac4GlcSH ligand shells. These AuNCs are active against both Gram‐negative and Gram‐positive bacteria, including multidrug‐resistant pathogens. Notably, an auranofin analogue, a mixed‐ligand 1.6 nm AuNC 4b, is more active than auranofin against Pseudomonas aeruginosa, while exhibiting lower toxicity against human A549 cells. The enhanced antibacterial activity of these AuNCs is characterized by a greater uptake of Au by the bacteria compared to AuI complexes. Additional factors include increased oxidative stress, moderate inhibition of thioredoxin reductase (TrxR), and DNA damage. Most intriguingly, the uptake of AuNCs are not affected by the bacterial outer membrane (OM) barrier or by binding with the extracellular proteins. This contrasts with AuI complexes like auranofin that are susceptible to protein binding and hindered by the OM barrier.

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“…Previous studies have shown that auranofin has a good safety profile [ 28 ]. Chronic exposure of patients to auranofin over extended periods of time was safe with no cumulative toxicity observed over five years [ 28 ].The usual adult dosage of auranofin is 6–9 mg daily for up to six months, which is a much longer course of treatment than what would be expected for auranofin as an antibacterial agent [ 20 , 49 ]. Consequently, the dose used in this study, (0.25 mg/kg), is within range of clinically-administered human doses.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, auranofin possesses antibacterial activity against Mycobacterium tuberculosis [ 26 ]. Auranofin also demonstrated antimicrobial activity against Gram-positive bacteria in different mouse models, including skin infection, systemic, and peritonitis models [ 18 , 20 , 21 , 25 – 27 ]. Auranofin is considered safe for systemic administration, with no serious side effects or long-term safety concerns [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Auranofin exerts antibacterial activity against Neisseria gonorrhoeae in a female mouse model of genital tract infection

2022

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Neisseria gonorrhoeae has been classified by the U.S. Centers for Disease Control and Prevention as an urgent threat due to the rapid development of antibiotic resistance to currently available antibiotics. Therefore, there is an urgent need to find new antibiotics to treat gonococcal infections. In our previous study, the gold-containing drug auranofin demonstrated potent in vitro activity against clinical isolates of N. gonorrhoeae, including multidrug-resistant strains. Therefore, the aim of this study was to investigate the in vivo activity of auranofin against N. gonorrhoeae using a murine model of vaginal infection. A significant reduction in N. gonorrhoeae recovered from the vagina was observed for infected mice treated with auranofin compared to the vehicle over the course of treatment. Relative to the vehicle, after three and five days of treatment with auranofin, a 1.04 (91%) and 1.40 (96%) average log10-reduction of recovered N. gonorrhoeae was observed. In conclusion, auranofin has the potential to be further investigated as a novel, safe anti-gonococcal agent to help meet the urgent need for new antimicrobial agents for N. gonorrhoeae infection.

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

Cited by 32 publications

References 44 publications

Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo

Ultrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo

Gold Nanoclusters as Nanoantibiotic Auranofin Analogues

Auranofin exerts antibacterial activity against Neisseria gonorrhoeae in a female mouse model of genital tract infection

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