Silicristin-mediated lethality towards Staphylococcus aureus: Evidence from oxidative stress contribution and molecular dynamics simulation

Beyond their primary role in modulating penicillin-binding proteins (PBPs), β-lactams have been linked to reactive oxygen species (ROS) generation in bacteria [ 1 ]. This effect on bacterial macromolecules presents a promising avenue for novel therapeutic development. This study explores the modulatory effect of silicristin on Staphylococcus aureus PBP2a and its potential to induce oxidative stress, both in silico and in vitro . Molecular dynamics (MD) simulations revealed that silicristin exhibited significant affinity (-25.61 kcal/mol) towards PBP2a binding domain compared to amoxicillin (-21.54 kcal/mol) over a 120-ns exposure period. This observation was further supported by the Density Functional Theory (DFT) B3LYP/6-31G+(dp) analysis, where silicristin demonstrated higher reactivity than cefotaxime, aligning with the thermodynamic stability and compactness of the resulting complexes. Further investigation through in vitro treatment of S. aureus ATCC 43300 with silicristin suggested an oxidative stress-mediated bactericidal effect, indicative of a greater impact through the Fenton reaction compared to the observation with amoxicillin. Notably, protein carbonyl and malondialdehyde levels were significantly elevated following silicristin treatment. Scanning electron microscopy further revealed extensive damage to the bacterial cell wall, with more pronounced blisters, eruptions, and sores in silicristin-treated cells than in both untreated and amoxicillin-treated cells. Additionally, oxidative stress triggered an SOS response, upregulating SordA and SoxR , with the strongest effect observed in silicristin-treated cells. These findings suggest that silicristin enhances redox stress in S. aureus and may be promising in designing novel β-lactam-based therapeutics against S. aureus -mediated infections. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany