Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging nosocomial pathogen among hospitalized patients, with high morbidity and mortality rates. The discovery of a novel antibacterial is urgently needed to address this resistance problem. The present study aims to explore the antibacterial potential of three depsidone compounds: 2-clorounguinol (1), unguinol (2), and nidulin (3), isolated from the marine sponge-derived fungus Aspergillus unguis IB1, both in vitro and in silico. The antibacterial activity of all compounds was evaluated by calculating the Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) against MRSA using agar diffusion and total plate count methods, respectively. Bacterial cell morphology changes were studied for the first time using scanning electron microscopy (SEM). Molecular docking, pharmacokinetics analysis, and molecular dynamics simulation were performed to determine possible protein–ligand interactions and the stability of the targeting penicillin-binding protein 2a (PBP2a) against 2-clorounguinol (1). The research findings indicated that compounds 1 to 3 exhibited MIC and MBC values of 2 µg/mL and 16 µg/mL against MRSA, respectively. MRSA cells displayed a distinct shape after the addition of the depsidone compound, as observed in SEM. According to the in silico study, 2-chlorounguinol exhibited the highest binding-free energy (BFE) with PBP2a (-6.7 kcal/mol). For comparison, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid inhibits PBP2a with a BFE less than −6.6 kcal/mol. Based on the Lipinski's rule of 5, depsidone compounds constitute a class of compounds with good pharmacokinetic properties, being easily absorbed and permeable. These findings suggest that 2-chlorounguinol possesses potential antibacterial activity and could be developed as an antibiotic adjuvant to reduce antimicrobial resistance.

耐甲氧西林金黄色葡萄球菌（MRSA）是住院患者中新出现的医院病原体，发病率和死亡率很高。迫切需要发现一种新型抗菌药物来解决这一耐药问题。本研究旨在探索从海洋海绵来源的真菌Aspergillus unguis IB1中分离出的三种缩苯酚化合物的抗菌潜力：2-clorounguinol ( 1 )、unguinol ( 2 ) 和 nidulin ( 3 )，无论是在体外还是在计算机模拟中。通过分别使用琼脂扩散法和总平板计数法计算针对 MRSA 的最低抑菌浓度 (MIC) 和最低杀菌浓度 (MBC) 来评估所有化合物的抗菌活性。首次使用扫描电子显微镜（SEM）研究细菌细胞形态变化。进行分子对接、药代动力学分析和分子动力学模拟，以确定可能的蛋白质-配体相互作用以及靶向青霉素结合蛋白 2a (PBP2a) 对 2-氯龙公酚 (2-clorounguinol) 的稳定性 (1 )。研究结果表明，化合物1至3对MRSA的MIC和MBC值分别为2μg/mL和16μg/mL。如 SEM 中观察到的，MRSA 细胞在添加缩酚酸化合物后显示出独特的形状。根据计算机研究，2-氯安吉醇与 PBP2a 表现出最高的自由结合能 (BFE) (-6.7 kcal/mol)。为了进行比较，(E)-3-(2-(4-氰基苯乙烯基)-4-oxoquinazolin-3(4H)-yl) 苯甲酸抑制 PBP2a，BFE 低于 -6.6 kcal/mol。基于Lipinski法则5，缩苯西酮类化合物构成一类具有良好药代动力学性质、易吸收、易渗透的化合物。这些发现表明，2-氯安吉醇具有潜在的抗菌活性，可以开发为抗生素佐剂以降低抗菌素耐药性。