Computational profiling of terpenoids for putative dual-target leads against Staphylococcus aureus penicillin binding protein 2a and beta-lactamase: An integrated structure-activity-relationship-based study

In Staphylococcus aureus, the penicillin-binding protein (PBP2a) and beta-lactamase (β-LTM) are primarily implicated in resistance to beta-lactam antibiotics, making them essential targets for the development of novel therapeutics. Terpenoids have proven to be a valuable source of antibiotics owing to their diversity, ability to target multiple bacterial pathways, and relatively low toxicity profiles. Herein, by employing a methodical blend of structure-based pharmacophore modelling, molecular docking, and ensemble-based docking analysis, five lead terpenoids (beta-amyrin, conferone, feselol, lantanolic acid, and quinovic acid) with higher binding tendencies for S. aureus PBP2a and β-LTM active sites, as well as the PBP2a allosteric site, were identified from a compiled library of 147,953 terpenoids. These leads also presented favourable in silico pharmacokinetic characteristics, drug likeness, and ADMET profiles. The thermostability investigation of the resulting complexes of the leads over a 180-ns molecular dynamics simulation revealed enhanced structural stability in the bound state. Relative to the reference standards, ceftaroline (−41.50 ± 6.11 kcal/mol) and clavulanate (−21.40 ± 4.7 kcal/mol), the most potent lead, quinovic acid (−47.09 ± 6.08 kcal/mol) against S. aureus PBP2a, as well as lantanolic acid (−35.35 ± 3.25 kcal/mol) and quinovic acid (−28.48 ± 4.99 kcal/mol) against S. aureus β-LTM, exhibited superior binding free energy, respectively. The principal component analysis (PCA) revealed more constrained motions in the bound structures compared to a wider range of conformational states in the unbound structures. Furthermore, quinovic acid, while being stabilised in the allosteric site of PBP2a, caused higher mobility of the gatekeeper residue, Tyr446, thereby suggesting an “opening” of the active site for therapeutic targeting. The favourable molecular orbital energies of the leads further suggest them as putative candidates to be further explored as therapeutics against multidrug-resistant S. aureus infections. Validatory studies are underway.