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Article

In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice

1
Nabriva Therapeutics GmbH, Leberstrasse 20, 1110 Vienna, Austria
2
Charles River Discovery, Portishead BS20 7AW, UK
3
PathCelerate Ltd., Cheshire CW4 8PW, UK
4
Nabriva Therapeutics US, Inc., Fort Washington, PA 19034, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(10), 5401; https://doi.org/10.3390/ijms25105401
Submission received: 8 April 2024 / Revised: 7 May 2024 / Accepted: 13 May 2024 / Published: 15 May 2024
(This article belongs to the Section Molecular Biology)

Abstract

Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant ‘low’ dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
Keywords: acute respiratory distress syndrome (ARDS); acute lung injury (ALI); community-acquired pneumonia; lefamulin; oseltamivir; azithromycin; antiviral; anti-inflammatory; lung histopathology; cytokines acute respiratory distress syndrome (ARDS); acute lung injury (ALI); community-acquired pneumonia; lefamulin; oseltamivir; azithromycin; antiviral; anti-inflammatory; lung histopathology; cytokines

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MDPI and ACS Style

Paukner, S.; Kimber, S.; Cumper, C.; Rea-Davies, T.; Sueiro Ballesteros, L.; Kirkham, C.; Hargreaves, A.; Gelone, S.P.; Richards, C.; Wicha, W.W. In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice. Int. J. Mol. Sci. 2024, 25, 5401. https://doi.org/10.3390/ijms25105401

AMA Style

Paukner S, Kimber S, Cumper C, Rea-Davies T, Sueiro Ballesteros L, Kirkham C, Hargreaves A, Gelone SP, Richards C, Wicha WW. In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice. International Journal of Molecular Sciences. 2024; 25(10):5401. https://doi.org/10.3390/ijms25105401

Chicago/Turabian Style

Paukner, Susanne, Sandra Kimber, Charlotte Cumper, Tina Rea-Davies, Lorena Sueiro Ballesteros, Christopher Kirkham, Adam Hargreaves, Steven P. Gelone, Claire Richards, and Wolfgang W. Wicha. 2024. "In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice" International Journal of Molecular Sciences 25, no. 10: 5401. https://doi.org/10.3390/ijms25105401

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