作者: Kaethner, Marc ; Preza, Matías ; Laleu, Benoît ; Vetter, Laura ; Bartetzko, Anissa ; Zumkehr, Trix ; Hemphill, Andrew ; Lundström-Stadelmann, Britta ; Zumstein, Pascal

Alveolar echinococcosis (AE) is a life-threatening disease caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis, primarily in the liver. Current drug treatments rely on benzimidazoles, which are not parasiticidal, requiring life-long therapy with significant side effects. Therefore, novel drug treatments are urgently needed. Drug repurposing offers a strategy to identify novel therapies against the neglected disease AE. We report on the in vitro screening of the Pandemic Response Box, an open-access compound library composed of 400 drug-like molecules assembled by Medicines for Malaria Venture (MMV) and the Drugs for Neglected Disease Initiative (DNDi), against E. multilocularis. An overview screen at 10 μM using the metacestode vesicle damage-marker release assay (based on release of phosphoglucose isomerase, PGI) and metacestode vesicle viability assay (based on ATP measurement) identified 37 active compounds. Reassessment in triplicates resulted in five active compounds (alexidine, carbendazim, ESI-09, MMV1581545, oxfendazole) displaying anti-metacestode activity. The parasiticidal activity of these five compounds was evaluated by ATP measurement in germinal layer cells. One compound, ESI-09, acted specifically against E. multilocularis (IC₅₀ on metacestode vesicles 6.06 ± 3.18 μM by PGI release assay and 2.09 ± 0.56 μM by metacestode vesicle viability assay as well as an IC₅₀ of 2.45 ± 0.86 μM on germinal layer cells) with a broad therapeutic window when compared to mammalian cell toxicity. Further experiments applying Seahorse technology and tetramethylrhodamine ethyl ester (TMRE) assay revealed that ESI-09 acts as a mitochondrial uncoupler in parasite cells. However, transmission electron microscopy showed no significant ultrastructural changes in parasite mitochondria, though increased secretion of extracellular vesicle-like structures between the tegument and the laminated layer was observed. In summary, screening of the Pandemic Response Box identified ESI-09 as a potential drug candidate for the treatment of AE. Further experiments are needed to evaluate the efficacy of ESI-09 in vivo.

2025-12-01·BRAZILIAN JOURNAL OF MICROBIOLOGY

Antimicrobial potential of compounds from the MMV pandemic response box and COVID box against carbapenem-resistant Acinetobacter baumannii

Article

作者: Rossato, Luana ; de Almeida de Souza, Gleyce Hellen ; Besson, Dominique ; Arantes, Julia Pimentel ; Sturaro, Mariana Carvalho ; Vicente, Jean Carlos Pael ; Melo, Andressa Leite Ferraz ; Martins, Aline Andrade ; Laleu, Benoît ; Simionatto, Simone ; de Cássia Cerqueira Melo, Rita

Antibiotic-resistant microorganisms, particularly carbapenem-resistant Acinetobacter baumannii (CRAB), are a significant threat to global public health due to limited treatment options. This study evaluated the antimicrobial potential and biofilm inhibition activities of 560 compounds from the Medicines for Malaria Venture (MMV) Pandemic Response Box and COVID Box against a multidrug-resistant CRAB strain. Compounds with a bacterial inhibition rate of ≥ 80% were further analyzed. The analyses included determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Additionally, their effects on biofilm inhibition, protein leakage, and synergy with meropenem were assessed. Among the tested compounds, 10 demonstrated notable antimicrobial activity, including doxycycline, atazanavir, alexidine, eravacycline, erythromycin, gepotidacin, trimetrexate, MMV1634402 (brilacidin), MMV1580854 and MMV1578564. Drugs such as doxycycline, gepotidacin, and eravacycline effectively inhibited biofilm formation at low concentrations, with inhibition rates of 33.05%, 40.99%, and 59.37%, respectively. Synergy testing revealed a strong synergistic effect (FICI = 0.37) between brilacidin and meropenem, enhancing antibacterial efficacy. The present study highlights the antimicrobial activity of MMV1634402 (brilacidin) and gepotidacin, providing preliminary evidence of their potential as therapeutic candidates against CRAB. However, further studies involving a broader range of isolates and clinical validation are essential to confirm their efficacy and safety.

2025-04-01·ACS Omega

Alexidine as a Potent Antifungal Agent Against Candida HemeuloniiSensu Stricto

Article

作者: Pimentel, Larissa Rodrigues ; Lucini, Fabiola ; Simionatto, Simone ; da Silva, Gabrieli Argueiro ; Rossato, Luana

The increasing prevalence of infections byCandida hemeulonii sensu stricto, particularly due to its resistance to standard antifungal therapies, represents a significant healthcare challenge. Traditional treatments often fail, emphasizing the need to explore alternative therapeutic strategies. Drug repurposing, which reevaluates existing drugs for new applications, offers a promising path. This study examines the potential of repurposing alexidine dihydrochloride as an antifungal agent againstC. hemeulonii sensu stricto. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) values were established using broth microdilution methods. To further assess antifungal activity, different assays were conducted, including growth inhibition, biofilm inhibition, biofilm eradication, and cell damage. Checkerboard assays were employed to study the compound's fungicidal potential and interactions with other antifungals. Additional tests, sorbitol protection assay, efflux pump inhibition, cell membrane permeability assays, and nucleotide leakage were performed. In vivo efficacy and safety were evaluated inTenebrio molitor larvae. Alexidine demonstrated fungicidal activity againstC. hemeulonii sensu stricto, with an MIC of 0.5 μg/mL. Biofilm formation was significantly inhibited, with a reduction of 78.69%. Mechanistic studies revealed nucleotide leakage, indicating membrane impact, but no significant protein leakage was detected. In vivo, alexidine displayed a favorable safety profile, with no evidence of hemolysis or acute toxicity in the T. molitor model. These findings support alexidine as a strong candidate for antifungal drug repurposing, especially for treatingC. hemeulonii sensu stricto infections. Its efficacy in inhibiting growth and biofilm formation, combined with a positive safety profile, underscores its potential for clinical development as an antifungal therapy.

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