Computational discovery of Allium sativum phytochemicals as dihydropteroate synthase inhibitors for combating Escherichia coli infections

The rise of antibiotic-resistant bacterial pathogens underscores the urgent need for novel therapeutics. Dihydropteroate synthase (DHPS) is a critical enzyme in the folate biosynthesis pathway of Escherichia coli, which represents a promising target due to its absence in humans and its susceptibility to inhibition by substrate analogues. While synthetic sulphnamides have historically targeted DHPS, resistance mechanisms and toxicity concerns necessitate alternative strategies. This study investigates bioactive phytoconstituents from Allium sativum (garlic) as potential DHPS inhibitors using computational approaches. A library of 120 phytochemicals from the IMPPAT database was screened against E. coli CFT073 DHPS. Two compounds, Kaempferol and Thiamine, were prioritised based on an integrated evaluation of docking performance, drug-likeness, ADMET filtering and interaction stability, with Kaempferol demonstrating favourable and comparable binding interactions relative to the reference inhibitor NSC170930. Subsequent all-atom molecular dynamics simulations revealed stable binding of Kaempferol and Thiamine to the DHPS active site and conserved interactions with catalytic residues. Pharmacokinetic profiling confirmed favourable drug-like properties and negligible toxicity risks. PASS predictions highlighted the potential antibacterial activities of these compounds. These findings position Kaempferol as the more promising scaffold for DHPS-targeted antibacterial development, while Thiamine should be considered a secondary hit requiring further optimisation because of its weaker binding and less favourable pharmacokinetic profile. Experimental validation is warranted to confirm their efficacy and safety.