Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition

Kingdon, Alexander D. H.; Meosa-John, Asti-Rochelle; Batt, Sarah M.; Besra, Gurdyal S.

doi:10.3389/fmicb.2023.1112491

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…Prior attempts to evaluate vanoxerine as an antimicrobial agent revealed antimycobacterial effects 24 . Disruption of the mycobacterial membrane, loss of membrane electrical potential, and the prevention of electrolyte efflux have been proposed as major mechanisms of vanoxerine's antimycobacterial activity, 25 and these same mechanisms may be responsible for its antifungal properties.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Repurposing of Pharmaceutical Agents as Antifungals:In vivoactivity againstCoccidioides

Mead,

Valentine,

Yin

et al. 2024

Preprint

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There is significant interest in identifying improved treatments for coccidioidomycosis, an endemic fungal infection found in the southwestern United States, and Central and South America. The current standard of care, fluconazole, often fails to completely eradicateCoccidioidesinfection; however, the cost of identifying new compounds is often high in terms of both finances and time. Therefore, repurposing existing pharmaceutical agents is an attractive option. In our previous work, we identified several compounds which inhibited fungal growthin vitro. Based on these findings, we screened a subset of these agents to increase the performance of fluconazole in a combination therapy approach, as compared to fluconazole alone, in a murine model. We observed that combination therapy of sertraline:fluconazole significantly reduced the amount of live fungus in the lung compared to fluconazole alone. These results suggest that sertraline can be repurposed as an adjunctive agent in the treatment of this important fungal disease.

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Section: Discussionmentioning

confidence: 99%

Discovery and Repurposing of Pharmaceutical Agents as Antifungals:In vivoactivity againstCoccidioides

Mead,

Valentine,

Yin

et al. 2024

Preprint

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Mechanisms of Triton X-100 reducing the Ag+-resistance of Enterococcus faecalis

Lv,

Duan,

Fan

et al. 2024

World J Microbiol Biotechnol

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In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides

Mead,

Valentine,

Yin

et al. 2024

Microbiol Spectr

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Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC 50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease. IMPORTANCE Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

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Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition

Cited by 3 publications

References 59 publications

Discovery and Repurposing of Pharmaceutical Agents as Antifungals:In vivoactivity againstCoccidioides

Discovery and Repurposing of Pharmaceutical Agents as Antifungals:In vivoactivity againstCoccidioides

Mechanisms of Triton X-100 reducing the Ag+-resistance of Enterococcus faecalis

In vitro small molecule screening to inform novel candidates for use in fluconazole combination therapy in vivo against Coccidioides

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