Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
SPR-based screening identifies luteolin from Artemisia scoparia as a potential PBP2a inhibitor with β-lactam-potentiating activity against MRSA.
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Zhang Dandan, Liu Xu, Wang Ruoliang, Tang Yuhang, Yang Doudou, Zhao Guanjie, Gao Yawen, Li Qian, Liang Yinku
Аннотация
BACKGROUND: Penicillin-binding protein 2a (PBP2a) is a major determinant of β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA). Natural PBP2a-binding compounds may serve as antibacterial adjuvants.
PURPOSE: To identify PBP2a-binding constituents from Artemisia scoparia and evaluate their anti-MRSA and β-lactam-potentiating activities.
STUDY DESIGN: A target-oriented workflow combining virtual screening, SPR-based molecular fishing, kinetic analysis, antibacterial synergy testing, and quantitative proteomics was established.
METHODS: Forty-four constituents were virtually screened, and recombinant PBP2a was immobilized on a CM5 sensor chip by EDC/NHS-mediated amine coupling for subsequent SPR-based molecular fishing coupled with LC-MS. Selected standards were analyzed using a 1:1 Langmuir kinetic model and molecular dynamics simulations. Luteolin was further evaluated by lysate-based thermal stability analysis, MIC determination, checkerboard assays, and DIA proteomics.
RESULTS: Thirty-three PBP2a-binding constituents were identified. Luteolin, chlorogenic acid, cynarin, and rutin showed comparatively stronger binding and formed stable complexes with PBP2a in molecular simulations. Luteolin inhibited MRSA with an MIC of 4 μg/mL and increased PBP2a thermal stability in an MRSA-derived protein environment. At 1 μg/mL, luteolin reduced the MICs of penicillin G and amoxicillin from 512 to 64 μg/mL, with FICI values of 0.375. Proteomics identified 363 differentially expressed proteins mainly associated with carbon metabolism, RNA degradation, RNA polymerase, and oxidative phosphorylation.
CONCLUSION: Luteolin is a potential PBP2a-targeting compound with β-lactam-potentiating activity against MRSA. Its effects may involve PBP2a interaction and broader metabolic and regulatory perturbations, although direct inhibition of PBP2a enzymatic activity remains unconfirmed.
PURPOSE: To identify PBP2a-binding constituents from Artemisia scoparia and evaluate their anti-MRSA and β-lactam-potentiating activities.
STUDY DESIGN: A target-oriented workflow combining virtual screening, SPR-based molecular fishing, kinetic analysis, antibacterial synergy testing, and quantitative proteomics was established.
METHODS: Forty-four constituents were virtually screened, and recombinant PBP2a was immobilized on a CM5 sensor chip by EDC/NHS-mediated amine coupling for subsequent SPR-based molecular fishing coupled with LC-MS. Selected standards were analyzed using a 1:1 Langmuir kinetic model and molecular dynamics simulations. Luteolin was further evaluated by lysate-based thermal stability analysis, MIC determination, checkerboard assays, and DIA proteomics.
RESULTS: Thirty-three PBP2a-binding constituents were identified. Luteolin, chlorogenic acid, cynarin, and rutin showed comparatively stronger binding and formed stable complexes with PBP2a in molecular simulations. Luteolin inhibited MRSA with an MIC of 4 μg/mL and increased PBP2a thermal stability in an MRSA-derived protein environment. At 1 μg/mL, luteolin reduced the MICs of penicillin G and amoxicillin from 512 to 64 μg/mL, with FICI values of 0.375. Proteomics identified 363 differentially expressed proteins mainly associated with carbon metabolism, RNA degradation, RNA polymerase, and oxidative phosphorylation.
CONCLUSION: Luteolin is a potential PBP2a-targeting compound with β-lactam-potentiating activity against MRSA. Its effects may involve PBP2a interaction and broader metabolic and regulatory perturbations, although direct inhibition of PBP2a enzymatic activity remains unconfirmed.