Isolation of butenolide compounds from endophytic Aspergillus terreus GDC2 associated with Garcinia cowa and their anti-MRSA activity: in vitro and in silico insights.

Two butenolide derivatives were isolated from the endophytic fungus Aspergillus terreus GCD2. Comprehensive 1D and 2D NMR spectroscopic analyses unequivocally established the structures of the isolated compounds as butyrolactone I (1) and aspernolide A (2). Among the isolates, compound 1 exhibited notable antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Molecular docking studies revealed that compound 1 strongly interacts with key MRSA resistance-associated proteins, including PBP2a, MecR1, and BlaR1, displaying the highest binding affinity towards PBP2a (-83.09 kcal/mol) compared with compound 2 and a reference oxoquinazolin derivative. These findings indicate effective targeting of the PBP2a-mediated resistance pathway. Molecular dynamics simulations further confirmed the structural stability of the compound 1 protein complexes, while ADME profiling suggested favourable lipophilicity and a drug-like metabolic profile involving CYP3A4 and CYP2C9. Collectively, this study highlights compound 1 as a promising lead candidate for the development of antibacterial drugs against MRSA.