Evaluation of the Anti-Mycobacterial and Anti-Inflammatory Activities of the New Cardiotonic Steroid γ-Benzylidene Digoxin-15 in Macrophage Models of Infection

Evaluation of the Anti-Mycobacterial and Anti-Inflammatory Activities of the New Cardiotonic Steroid γ-Benzylidene Digoxin-15 in Macrophage Models of Infection

Cardiotonic steroids modulate various aspects of the inflammatory response. The synthetic cardiotonic steroid γ-benzylidene digoxin 15 (BD-15), a digoxin derivative, has emerged as a promising candidate with potential immunomodulatory effects. However, its biological activity remains largely unexplo...

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Main Authors: Daniel Wilson A. Magalhães, Maria Gabriella S. Sidrônio, Noêmia N. A. Nogueira, Deyse Cristina Madruga Carvalho, Maria Eugênia G. de Freitas, Ericke Cardoso Oliveira, Gustavo F. de Frazao Lima, Demétrius A. M. de Araújo, Cristoforo Scavone, Thalisson Amorim de Souza, José Augusto F. P. Villar, Leandro A. Barbosa, Francisco Jaime Bezerra Mendonça-Junior, Valnês S. Rodrigues-Junior, Sandra Rodrigues-Mascarenhas
Format: Article
Language:English
Published: MDPI AG 2025-01-01
Series:Microorganisms
Subjects:
tberculosis
drug development
host-directed therapy
anti-inflammatory
benzylidene digoxin
Online Access:https://www.mdpi.com/2076-2607/13/2/269
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Summary:Cardiotonic steroids modulate various aspects of the inflammatory response. The synthetic cardiotonic steroid γ-benzylidene digoxin 15 (BD-15), a digoxin derivative, has emerged as a promising candidate with potential immunomodulatory effects. However, its biological activity remains largely unexplored. This study investigated the anti-mycobacterial and anti-inflammatory effects of BD-15 in an in vitro macrophage infection model with <i>Mycobacterium</i> spp. Unlike digoxin, which showed significant toxicity at higher concentrations, BD-15 exhibited no cytotoxicity in RAW 264.7 cells (a murine macrophage cell line). Both compounds were evaluated in <i>Mycobacterium smegmatis</i>-infected RAW 264.7 cells, reducing bacterial burden without direct bactericidal activity. Additionally, both modulated pro-inflammatory cytokine levels, notably by decreasing tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels. BD-15 specifically reduced NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome expression and increased interleukin-10 (IL-10) production. Notably, BD-15 reduced colony-forming unit (CFU) counts in <i>Mycobacterium tuberculosis</i>-infected RAW 264.7 cells. Toxicity assays in HepG2 cells (a human liver cancer cell line) showed that BD-15 had minimal hepatotoxicity compared to digoxin, and both demonstrated negligible acute toxicity in an <i>Artemia salina</i> bioassay. These findings revealed the immunomodulatory effects of cardiotonic steroids in a bacterial infection model and highlighted BD-15 as a safer alternative to digoxin for therapeutic applications.
ISSN:2076-2607

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