SARS-CoV-2 infection enhancement by Amphotericin B: Implications for disease management

Nguyen, D.; Laidlaw, S. M.; Dong, X.; Wand, M. E.; Horton, A.; Sutton, M.; Tree, J.; Milligan, R.; Erdmann, M.; Matthews, D. A.; Davidson, A. D.; Rahman, K. M.; Hiscox, J. A.; Carroll, M. W.

doi:10.1101/2024.11.07.622419

bioRxiv · 10.1101/2024.11.07.622419

SARS-CoV-2 infection enhancement by Amphotericin B: Implications for disease management

Nguyen, D.·Laidlaw, S. M.·Dong, X.·Wand, M. E.·Horton, A.·Sutton, M.·Tree, J.·Milligan, R.·Erdmann, M.·Matthews, D. A.·Davidson, A. D.·Rahman, K. M.·Hiscox, J. A.·Carroll, M. W.

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Abstract

Severe coronavirus disease 2019 (COVID-19) patients who require hospitalisation are at high risk of invasive pulmonary mucormycosis. Amphotericin B (AmB), which is the first line therapy for invasive pulmonary mucormycosis, has been shown to promote or inhibit replication of a spectrum of viruses. In this study, we first predicted that AmB and Nystatin had strong interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins using in silico screening, indicative of drugs with potential therapeutic activity against this virus. Subsequently, we investigated the impact of AmB, Nystatin, Natamycin, Fluconazole and Caspofungin on SARS-CoV-2 infection and replication in vitro. Results showed that AmB and Nystatin actually increased SARS-CoV-2 replication in Vero E6, Calu-3 and Huh7 cells. At optimal concentrations, AmB and Nystatin increase SARS-CoV-2 replication by up to 100- and 10-fold in Vero E6 and Calu-3 cells, respectively. The other antifungals tested had no impact on SARS-CoV-2 infection in vitro. Drug kinetic studies indicate that AmB enhances SARS-CoV-2 infection by promoting viral entry into cells. Additionally, knockdown of genes encoding for interferon-induced transmembrane (IFITM) proteins 1, 2, and 3 suggests AmB enhances SARS-CoV-2 cell entry by overcoming the antiviral effect of the IFITM3 protein. This study further elucidates the role of IFITM3 in viral entry and highlights the potential dangers of treating COVID-19 patients, with invasive pulmonary mucormycosis, using AmB. ImportanceAmB and Nystatin are common treatments for fungal infections but were predicted to strongly interact with SARS-CoV-2 proteins, indicating their potential modulation or inhibition against the virus. However, our tests revealed that these antifungals, in fact, enhance SARS-CoV-2 infection by facilitating viral entry into cells. The magnitude of enhancement could be up to 10- or 100-fold depending on cell lines used. These findings indicate that AmB and Nystatin have the potential to enhance disease when given to patients infected with SARS-CoV-2 and therefore should not be used for treatment of fungal infections in active COVID-19 cases.

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Nguyen, D., Laidlaw, S. M., Dong, X., Wand, M. E., Horton, A., Sutton, M., Tree, J., Milligan, R., Erdmann, M., Matthews, D. A., Davidson, A. D., Rahman, K. M., Hiscox, J. A., Carroll, M. W.. 2024-11-07. SARS-CoV-2 infection enhancement by Amphotericin B: Implications for disease management. https://doi.org/10.1101/2024.11.07.622419

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