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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Influenza A Virus, H1N1 Subtype*/drug effects ; Mice, Inbred BALB C* ; Orthomyxoviridae Infections*/drug therapy ; Orthomyxoviridae Infections*/immunology ; Orthomyxoviridae Infections*/virology ; Disease Models, Animal* ; Diterpenes*/pharmacology ; Diterpenes*/therapeutic use; Animals ; Mice ; Cytokines/metabolism ; Azithromycin/pharmacology ; Azithromycin/therapeutic use ; Oseltamivir/pharmacology ; Oseltamivir/therapeutic use ; Female ; Lung/immunology ; Lung/virology ; Lung/drug effects ; Lung/pathology ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Tetrahydronaphthalenes/pharmacology ; Tetrahydronaphthalenes/therapeutic use ; Respiratory Distress Syndrome/drug therapy ; Respiratory Distress Syndrome/immunology ; Respiratory Distress Syndrome/virology ; Immunomodulating Agents/pharmacology ; Immunomodulating Agents/therapeutic use ; Bronchoalveolar Lavage Fluid/immunology ; Polycyclic Compounds ; Thioglycolates

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 (TCID 50 ) 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.

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882391 Austrian Research Promotion Agency

Keywords: acute lung injury (ALI); acute respiratory distress syndrome (ARDS); anti-inflammatory; antiviral; azithromycin; community-acquired pneumonia; cytokines; lefamulin; lung histopathology; oseltamivir

0 (Diterpenes)
21904A5386 (lefamulin)
0 (Cytokines)
83905-01-5 (Azithromycin)
20O93L6F9H (Oseltamivir)
0 (Antiviral Agents)
0 (Tetrahydronaphthalenes)
0 (Immunomodulating Agents)
0 (Polycyclic Compounds)
0 (Thioglycolates)

Date Created: 20240525 Date Completed: 20240525 Latest Revision: 20240527

20240527

PMC11121702

10.3390/ijms25105401

38791439