Unveiling novel therapeutic targets and potent hits to combat antimicrobial resistance in Bacteroides fragilis.

Abstract

The opportunistic anaerobic bacterium Bacteroides fragilis is an important human pathogen associated with a variety of infections, including intra-abdominal abscesses, peritonitis, bacteremia, lung abscesses and surgical site infections. The growing number of strains that are multidrug-resistant (MDR) in B. fragilis has raised attention to identify new therapeutic targets and discover potent antimicrobial drugs. An integrative computational approach was used in this study to highlight promising inhibitors against B. fragilis and identify potential therapeutic targets. The present study identified 18 essential proteins from the B. fragilis proteome that contribute to virulence and pathogenicity and play critical roles in bacterial survival. Furthermore, protein-protein interactions (PPI's) network analysis, functional annotation, and enrichment analyses identified tetraacyldisaccharide 4'-kinase (LpxK) as the most promising druggable target, owing to its essential role in lipopolysaccharide (LPS) biosynthesis in Gram-negative bacteria. Structure-guided drug design identified five high-affinity LpxK inhibitors. DFT and molecular dynamics analyses confirmed stable binding and conformational stability. Furthermore, these findings provide a theoretical basis for the rational development of targeted antibacterial agents against multidrug-resistant B. fragilis towards infectious disease control, and lay the foundation for future experimental evaluation and optimization.

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