Repurposing Drugs as Bacteroides fragilis BFT-3 Inhibitors in the Animal Infection Model Galleria mellonella
Ana Jiménez-Alesanco1,2, Marta Gómara-Lomero2, Hajar Jeblaoui1,3
1Institute of Biocomputation and Physics of Complex Systems (BIFI), Universidad de Zaragoza, Zaragoza, Spain.
Abstract:
Bacteroides fragilis is a key component of the human gut microbiota, although enterotoxigenic strains (ETBF), which produce B. fragilis toxin (BFT), can act as opportunistic pathogens. BFT disrupts intestinal epithelial integrity and contributes to conditions such as inflammatory bowel disease and colorectal cancer. This study aimed to characterize three allosteric inhibitors of BFT-3 (isoform 3 of BFT), previously identified by our group through high-throughput screening of US Food and Drug Administration approved drugs. We evaluated their activities in vitro and in vivo. Using Galleria mellonella larvae as a novel infection model for B. fragilis, we assessed the antimicrobial and antivirulence potential of these compounds. Among the three tested compounds, MOA4 demonstrated superior efficacy, enhanced bacterial clearance in vivo, and increased larval survival in a dose-dependent manner, with minimal toxicity. Synergy studies have revealed the potential combinatory effects of MOA4 and conventional antibiotics. These findings establish G. mellonella as a valuable alternative model for studying B. fragilis infections and highlight MOA4 as a promising candidate to be repurposed for the treatment of B. fragilis-mediated diseases while preserving commensal microbiota.
Insights
A novel drug, MOA4, effectively targets the B. fragilis toxin (BFT) in a new infection model. This compound shows promise for treating diseases caused by enterotoxigenic B. fragilis (ETBF) while preserving beneficial gut bacteria.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Enterotoxigenic Bacteroides fragilis (ETBF) produces B. fragilis toxin (BFT), disrupting gut epithelial integrity.
- BFT is implicated in inflammatory bowel disease and colorectal cancer.
- Targeting BFT is crucial for managing ETBF-associated pathologies.
Purpose of the Study:
- To characterize three allosteric inhibitors of BFT-3.
- To evaluate the in vitro and in vivo efficacy of these inhibitors.
- To establish Galleria mellonella as a model for B. fragilis infection studies.
Main Methods:
- High-throughput screening of FDA-approved drugs to identify BFT inhibitors.
- In vitro and in vivo testing of identified compounds using Galleria mellonella larvae.
- Assessment of antimicrobial and antivirulence potential, bacterial clearance, and host survival.
- Synergy studies with conventional antibiotics.
Main Results:
- MOA4 demonstrated superior efficacy among the tested compounds.
- MOA4 significantly enhanced bacterial clearance and increased larval survival in a dose-dependent manner.
- MOA4 exhibited minimal toxicity and potential synergistic effects with antibiotics.
Conclusions:
- Galleria mellonella serves as a valuable model for studying B. fragilis infections.
- MOA4 is a promising candidate for repurposing to treat B. fragilis-mediated diseases.
- MOA4 may help preserve commensal microbiota during treatment.
