Alharbi Ohood S, Alharbi Mohanned Talal, A Ismail Mazen, Sait Ahmad M, Mufrrih Mohammed, Alhazmi Wafaa, Saleh Bandar Hasan, Zubair Manal A, Juma Noha A, Helmi Noof R, Niyazi Hatoon A, Niyazi Hanouf A, Daghistani Hussam, Shamrani Taghreed, Halabi Waiel S, Alfadil Abdalbagi, Altayb Hisham N, Ibrahem Karem
Department of Microbiology and Parasitology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Department of Basic Medical Sciences, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia.
Biomol Biomed. 2025 Apr 1;25(10):2335-2344. doi: 10.17305/bb.2025.11886.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen causing infections ranging from skin disorders to severe conditions like infective endocarditis. Its evolving resistance, including resistance to β-lactams and last-resort antibiotics, such as vancomycin, daptomycin, and linezolid, necessitates alternative therapies. This study investigates the synergistic efficacy of vancomycin and 3-hydrazinoquinoxaline-2-thiol (3HL) against 23 clinical MRSA isolates. Susceptibility testing was performed using broth microdilution and checkerboard assays, while in silico analyses assessed interactions between vancomycin and 3HL. Vancomycin exhibited minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL, whereas 3HL showed higher MICs of 16-32 µg/mL. Synergistic interactions were confirmed via checkerboard assays, with fractional inhibitory concentration index (FICI) values between 0.236 and 0.5, indicating enhanced vancomycin efficacy. Notably, vancomycin MICs decreased significantly when combined with 3HL. In silico docking revealed interactions with penicillin-binding protein 2a (PBP2a), suggesting promising therapeutic potential. Vancomycin exhibited superior docking scores (-8.9 kcal/mol) and stabilizing hydrogen bonds, effectively targeting key protein grooves. Both compounds demonstrated potential for overcoming PBP2a's structural occlusions, suggesting their role in combating β-lactam-resistant strains through targeted protein inhibition and structural stabilization.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种主要病原体，可引发从皮肤疾病到感染性心内膜炎等严重病症的感染。其不断演变的耐药性，包括对β-内酰胺类抗生素以及万古霉素、达托霉素和利奈唑胺等最后手段抗生素的耐药性，使得需要 alternative therapies。本研究调查了万古霉素和3-肼基喹喔啉-2-硫醇（3HL）对23株临床MRSA分离株的协同疗效。使用肉汤微量稀释法和棋盘法进行药敏试验，同时通过计算机分析评估万古霉素和3HL之间的相互作用。万古霉素的最低抑菌浓度（MIC）范围为0.25至1μg/mL，而3HL的MIC较高，为16 - 32μg/mL。通过棋盘法确认了协同相互作用，分数抑菌浓度指数（FICI）值在0.236至0.5之间，表明万古霉素的疗效增强。值得注意的是，与3HL联合使用时，万古霉素的MIC显著降低。计算机对接显示与青霉素结合蛋白2a（PBP2a）相互作用，表明具有良好的治疗潜力。万古霉素表现出优异的对接分数（-8.9 kcal/mol）和稳定的氢键，有效地靶向关键蛋白凹槽。两种化合物都显示出克服PBP2a结构阻塞的潜力，表明它们通过靶向蛋白抑制和结构稳定在对抗β-内酰胺耐药菌株中的作用。
