Exosomes delivering a high-throughput-screened RNA polymerase inhibitor for highly effective therapy of multidrug-resistant bacterial infected pneumonia.
Epirubicin demonstrated 99% eradication of multidrug-resistant bacteria in vitro and in murine models within 12 hours, suggesting potential for further development against bacterial pneumonia.
Where it sits
this study against the rest of the epitalon (epithalon) corpusSummary and findings
This study evaluated the antibacterial efficacy of the repurposed semi-synthetic anthracycline hydrochloride Epirubicin (EPI) against multidrug-resistant bacterial pneumonia. EPI was tested at a concentration of 8 μg/mL in vitro, achieving 99% eradication of S. aureus and MDR E. coli within 12 hours. Additionally, Exo/EPI demonstrated similar efficacy in murine pneumonia models, clearing 99% of bacteria within the same timeframe.
Abstract
Bacterial pneumonia remains a primary global health threat, necessitating the development of novel therapeutic strategies to overcome escalating antibiotic resistance. In this study, we identified a highly active bacterial RNAP inhibitor, the repurposed semi-synthetic anthracycline hydrochloride Epirubicin (EPI), via the in silico high-throughput screening of a commercial library containing 16,563 small molecules. We identified EPI as a potent multi-target antibacterial agent. Alongside its intrinsic DNA intercalation properties, EPI heavily interferes with RNAP by targeting conserved catalytic residues (LYS838 and ASP1003), destabilizing the RNAP structure through a mechanism distinct from rifampicin. <i>In vitro</i>, EPI (8 μg/mL) achieved 99% eradication of <i>S. aureus</i> and multidrug-resistant (MDR) <i>E. coli</i> within 12 h by disrupting carbohydrate metabolism and ATP synthesis. To enhance clinical efficacy, EPI was encapsulated in stem cell-derived exosomes (Exo/EPI). In murine pneumonia models, the Exo/EPI nanoplatform cleared 99% of bacteria within 12 h. Furthermore, the platform rapidly attenuated infection-induced pulmonary inflammation, evidenced by a marked reduction in inflammatory cell infiltration, while significantly accelerating structural lung tissue repair and preventing cellular apoptosis via organized collagen deposition. This integrated strategy of computational discovery and exosomes delivery provides a blueprint for developing multifunctional antimicrobials against MDR infections.
Background
Bacterial pneumonia is a significant global health issue, exacerbated by rising antibiotic resistance. Previous research has highlighted the need for innovative therapeutic strategies to combat multidrug-resistant infections. This study aims to explore the potential of a high-throughput-screened RNA polymerase inhibitor, Epirubicin, as a novel treatment approach.
Methods
The study utilized in silico high-throughput screening of a commercial library of 16,563 small molecules to identify EPI as a potent antibacterial agent. EPI was tested in vitro at a concentration of 8 μg/mL and evaluated for its effects on S. aureus and MDR E. coli. The efficacy of EPI was further assessed in murine pneumonia models using an exosome delivery system.
Results
EPI achieved 99% eradication of S. aureus and MDR E. coli within 12 hours at a concentration of 8 μg/mL. In murine models, the Exo/EPI platform also cleared 99% of bacteria within 12 hours, indicating a rapid antibacterial effect.
Interpretation
The findings suggest that EPI has significant antibacterial properties, particularly against multidrug-resistant strains. While the statistical significance of the results is clear, the clinical relevance remains uncertain due to the lack of human data and potential confounding factors inherent in animal studies. The study provides a promising avenue for further research into multifunctional antimicrobials.
Key findings
- EPI (8 μg/mL) achieved 99% eradication of S. aureus and MDR E. coli within 12 h.
- Exo/EPI cleared 99% of bacteria within 12 h in murine pneumonia models.
Limitations
- in vitro and murine models only, no human data
- single concentration of EPI tested
- short follow-up duration of 12 hours