Computational Insight into Biofilm Inhibitory Activity of Ketidocillinone B and C against Pseudomonas aeruginosa: A Computational Study

Lymphatic filariasis (LF) remains a significant public health challenge, particularly in endemic regions where secondary bacterial infections exacerbate the morbidity associated with chronic lymphedema. Among these infections, Pseudomonas aeruginosa stands out due to its biofilm-forming ability and resistance to conventional antibiotics. This study underscores the importance of targeting P. aeruginosa in LF patients, as biofilm-associated infections are prevalent in chronic wounds, complicating treatment and increasing healthcare burdens. Leveraging molecular docking and molecular dynamics simulations, we screened 100 fungal polyketides against LasR and PqsR, quorum-sensing proteins critical to P. aeruginosa biofilm formation. Ketidocillinone B (Ket B) and Ketidocillinone C (Ket C) emerged as promising candidates with notable binding affinities of -9.3 kcal/mol and − 9.5 kcal/mol to LasR, and − 7.9 kcal/mol and − 8.8 kcal/mol to PqsR, respectively. Molecular dynamics simulations revealed sustained stability of both compounds within the active sites, with binding energies of -82.559 kJ/mol (Ket B) and − 68.680 kJ/mol (Ket C) for LasR, and − 86.855 kJ/mol (Ket B) and − 90.342 kJ/mol (Ket C) for PqsR. Pharmacokinetic evaluations indicated high gastrointestinal absorption, solubility, and favorable metabolic profiles, with Ket B exhibiting a clearance rate of 16.306 mL/min/kg and Ket C 14.881 mL/min/kg. These findings highlight the potential of Ket B and Ket C as therapeutic agents against P. aeruginosa infections in LF patients, through computational investigation. Future experimental validation could help by offering a novel approach to mitigate complications associated with this neglected tropical disease using KetB and Ket C as starting scaffold.