Designing Novel Antibiotics against Pseudomonas aeruginosa to Tackle Antimicrobial Drug Resistance: Structure-based Drug Design of Inhibitors of t-RNA Methyltransferases (trmA) from Pseudomonas aeruginosa

Background:: The global emergence of antibiotic resistance among pathogenic bacteria presents a severe threat to public health. Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, exhibits robust intrinsic and acquired resistance mechanisms against various antibiotics. Recent studies have implicated post-transcriptional modifications of transfer RNA (tRNA) in contributing to this resistance, making tRNA-modifying enzymes like trmA, a potential therapeutic target. Objective: This study aims to identify potential inhibitors of trmA to disrupt essential cellular processes and counter antibiotic resistance. Methods: A structure-based virtual screening approach was employed to evaluate a series of compounds structurally similar to S-adenosylmethionine, a universal methyl group donor and known binder of trmA. Molecular dynamics (MD) simulations were performed for the top docked complexes to analyze conformational dynamics resulting from inhibitor binding to trmA. Results: Compound 24762163 was identified as a top candidate through virtual screening and subsequent MD simulations. Its binding efficiency and conformational stability suggest that it has a significant potential as a trmA inhibitor. Conclusion: Compound 24762163 demonstrates promise as an innovative therapeutic intervention to combat antibiotic resistance in Pseudomonas aeruginosa by targeting tRNA-modifying methyltransferases. This study highlights the potential of trmA inhibitors as a novel strategy to address the growing threat of antibiotic-resistant pathogens.