Repurposing ebselen for decolonization of vancomycin-resistant enterococci (VRE)

Abstract

Enterococci represent one of the microbial world’s most challenging enigmas. Colonization of the gastrointestinal tract (GIT) of high-risk/immunocompromised patients by enterococci exhibiting resistance to vancomycin (VRE) can lead to life-threating infections, including bloodstream infections and endocarditis. Decolonization of VRE from the GIT of high-risk patients represents an alternative method to suppress the risk of the infection. It could be considered as a preventative measure to protect against VRE infections in high-risk individuals. Though multiple agents (ramoplanin and bacitracin) have been evaluated clinically, no drugs are currently approved for use in VRE decolonization of the GIT. The present study evaluates ebselen, a clinical molecule, for use as a decolonizing agent against VRE. When evaluated against a broad array of enterococcal isolates in vitro, ebselen was found to be as potent as linezolid (minimum inhibitory concentration against 90% of clinical isolates tested was 2 μg/ml). Though VRE has a remarkable ability to develop resistance to antibacterial agents, no resistance to ebselen emerged after a clinical isolate of vancomycin-resistant E. faecium was serially-passaged with ebselen for 14 days. Against VRE biofilm, a virulence factor that enables the bacteria to colonize the gut, ebselen demonstrated the ability to both inhibit biofilm formation and disrupt mature biofilm. Furthermore, in a murine VRE colonization reduction model, ebselen proved as effective as ramoplanin in reducing the bacterial shedding and burden of VRE present in the fecal content (by > 99.99%), cecum, and ileum of mice. Based on the promising results obtained, ebselen warrants further investigation as a novel decolonizing agent to quell VRE infection.

Repurposing Salicylamide for Combating Multidrug-Resistant Neisseria gonorrhoeae

“…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.…”

tert-Butylphenylthiazoles with an oxadiazole linker: a novel orally bioavailable class of antibiotics exhibiting antibiofilm activity

“…At the outset of this study, the initial antibacterial screening was performed on methicillinresistant Staphylococcus aureus (MRSA, 2658 RCMB). The results presented in Table 1 indicated that the 2-amino-1,3,4oxadiazole linker with aliphatic side chains (compounds [8][9][10][11][12][13][14][15][16][17] is void of anti-MRSA activity.…”

Anti-virulence strategies for Clostridioides difficile infection: advances and roadblocks

“…Against vancomycin-resistant enterococci (VRE), Ebselen exhibited potent bactericidal activity in vitro , and a distinct lack of Ebselen-resistant VRE after prolonged passaging. 81 As with multidrug-resistant staphylococcal biofilms, Ebselen was shown to significantly reduce established VRE biofilms. 81 With the antimicrobial activity demonstrated against other notable pathogens, it becomes an attractive option to explore as an antimicrobial against CD.…”

“… 81 As with multidrug-resistant staphylococcal biofilms, Ebselen was shown to significantly reduce established VRE biofilms. 81 With the antimicrobial activity demonstrated against other notable pathogens, it becomes an attractive option to explore as an antimicrobial against CD. Work by Bender et al 80 and Beilhartz et al 82 identified and demonstrated the ability of Ebselen to inhibit the activity of CD toxins.…”