Molecular Insights into Metformin and Ceftriaxone Combination against Gastroenteritis: Multifaceted Actions Revealed by Network Pharmacology.

Abstract

Background: Network pharmacology (NP) investigates the multifaceted actions of drugs across various targets, aiding drug discovery for complex diseases like gastroenteritis (GE). Metformin (MET) has antihyperglycemic and potential antimicrobial effects, while ceftriaxone (CEF) is effective against gram-negative strains but prone to resistance. Combining CEF with MET may synergize their antimicrobial effects, potentially reducing doses and resistance. Objective: To predict the potential synergy between MET-CEF combination against GE using NP approaches Methods: Pharmacodynamic gene targets of MET and CEF were predicted via Swiss Target Prediction, Pharmapper, and SEA Search Server. GE-associated genes were sourced from DisGeNET, OMIM, and GeneCard databases. Intersection genes between drugs and GE were determined using Venny 2.1. Protein-protein interaction (PPI) network was constructed using the STRING database. The resulting network was analyzed using Cytoscape. Cytoscape’s cytoHubba v0.1 was used to determine the top ten interacting genes. Subsequent analysis involved Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Results: The study revealed 188, 194, and 382 potential target genes for MET, CEF, and the MET-CEF combination, respectively, with 988 genes associated with GE. The intersection of target genes between GE and MET, CEF, or the MET-CEF combination was 27, 43, and 55, respectively, indicating broader gene modulation with the MET-CEF combination compared to individual drugs. The PPI network comprised 55 nodes and 376 edges, with CASP3, interleukin 2, and NFκB1 identified as the most interacting genes, predominantly involved in cellular apoptotic and inflammatory pathways. The primary biological process targeted by the MET-CEF combination was the regulation of the inflammatory response. Enriched pathways included Yersinia infection, PD-L1 expression, PD-1 Checkpoint pathway, and C-type lectin receptor signalling, associated with GE pathophysiology. Conclusions: The MET-CEF combination has the potential to target multiple pathways associated with GE pathophysiology, indicating its enhanced efficacy as a promising therapeutic option for GE treatment with potential synergistic effects.