A systematic toxicity evaluation of cephalosporins via transcriptomics in zebrafish and in silico ADMET studies

Area of Science:

• Pharmacology and Toxicology
• Developmental Biology
• Genomics

Background:

• Cephalosporins are widely used beta-lactam antibiotics.
• Limited data exists on zebrafish toxicity of specific cephalosporin structures.
• Cephalosporins containing an N-methyltetrazolthio ring at the C-3 position (CNMTs) are of particular interest.

Purpose of the Study:

• To investigate the toxicity of CNMTs on zebrafish embryos.
• To compare in vivo zebrafish toxicity with in silico predictions.
• To identify molecular pathways affected by CNMTs exposure.

Main Methods:

• Exposure of zebrafish embryos to varying concentrations of CNMTs.
• Assessment of mortality and malformation rates.
• Transcriptomic analysis to measure gene expression changes (has1, cnnm2a) and identify differentially expressed genes (DEGs).
• In silico toxicity prediction analysis.

Main Results:

• CNMTs toxicity was concentration-dependent, aligning with in silico predictions.
• Significant changes in has1 and cnnm2a gene expression were observed.
• Enriched pathways included neuroactive ligand-receptor interactions, cardiac, and vascular smooth muscle contraction.
• C-3 and C-7 substituents of 7-aminocephalosporanic acid (7-ACA) were linked to toxicity at different concentrations.

Conclusions:

• Zebrafish embryos provide a robust model for evaluating chemical toxicity and structure-activity relationships.
• Transcriptomic analysis aids in identifying target organ toxicity.
• The study enhances drug safety assessment methodologies.