Machine learning-based virtual screening and density functional theory characterisation of natural inhibitors...

Streptococcus pneumoniae (S. pneumoniae) has developed resistance to β-lactam antibiotics, largely due to mutations in penicillin-binding protein 2x (PBP2x), particularly within conserved motifs such as STMK and KSG. PBP2x mutations are frequently reported in multidrug-resistant pneumococcal strains associated with pneumonia, meningitis, and septicaemia. especially in serotypes 19A, 19F, and 23F, showing reduced susceptibility to β-lactam antibiotics. These mutations in the PBP2x disrupt antibiotic binding and enzymatic functions, highlighting the need for alternative therapeutic strategies. This study focused on five clinically relevant PBP2x mutations (T338A/G/P and K547G/T) within its active site. A library of phytocompounds was screened using a machine learning model trained to identify antibacterial compounds. Top candidates were filtered based on ADMET properties, and their electronic characteristics were assessed using HOMO-LUMO analysis and electrostatic potential mapping, through density functional theory (DFT). Glucozaluzanin C, a phytochemical derived from Elephantopus scaber, emerged as a potential candidate. Molecular docking and dynamics simulations revealed strong binding affinity and structural integrity with all PBP2x mutants, over a 100-ns timescale. RMSD, RMSF, and hydrogen bonding analysis confirmed stable interactions, suggesting Glucozaluzanin C may effectively interact with PBP2x mutants. Overall, the study highlights an effective strategy for identifying plant-derived inhibitors against β-lactam-resistant S. pneumoniae.