通过药物再利用和联合治疗鉴定耐甲氧西林金黄色葡萄球菌的潜在PBP2a抑制剂

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fangfang Jiao, Pinkai Wang, Derong Zeng, Yiqiong Bao, Yan Zhang, Jun Tao, Jingjing Guo
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引用次数: 0

摘要

耐甲氧西林金黄色葡萄球菌(MRSA)通过表达青霉素结合蛋白2a (PBP2a)实现对β-内酰胺类抗生素的高水平耐药,该蛋白具有阻断抗生素结合的封闭活性位点。在此,我们实施了一种将药物再利用与协同治疗相结合的策略,从fda批准的药物数据库中识别针对PBP2a变抗部位的潜在抑制剂。最初,采用不同的滑翔对接方法(HTVS、SP和XP)和两种具有代表性的PBP2a结构进行了回顾性验证。Glide SP与一种具有代表性的PBP2a构象的组合在识别活性化合物方面表现出最高的功效。然后利用优化后的参数筛选fda批准的药物,最终有15种化合物入围,可与头孢唑林(一种无效的抗MRSA头孢菌素)联合治疗。通过生物assays-checkerboard time-kill化验和生活/死亡细菌staining-we发现四个化合物表现出强劲的杀菌活性(FICI & lt; 0.5)相比,未经处理的控制和单一疗法与头孢唑林。扫描电镜(SEM)证实,虽然头孢唑林单独对MRSA细胞没有造成明显的损伤,但联合治疗明显诱导细胞裂解。另外的MM-GBSA研究强调了米托蒽醌与变构位点的强结合亲和力。这些发现介绍了一种联合治疗方法,有可能恢复MRSA对β-内酰胺类抗生素的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy

Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy

Methicillin-resistant Staphylococcus aureus (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented a strategy that combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric site from an FDA-approved drug database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) and two representative PBP2a structures. The combination of Glide SP and one representative PBP2a conformation showed the highest efficacy in identifying active compounds. The optimized parameters were then utilized to screen FDA-approved drugs, and 15 compounds were shortlisted for potential combination therapy with cefazolin, an ineffective cephalosporin against MRSA. Through biological assays—checkerboard, time-kill assays, and live/dead bacterial staining—we discovered that four compounds exhibited robust bactericidal activity (FICI < 0.5) compared to both untreated control and monotherapy with cefazolin alone. Scanning electron microscopy (SEM) confirmed that while cefazolin alone did not cause visible damage to MRSA cells, the combination treatment markedly induced cell lysis. Additional MM-GBSA studies underscored the strong binding affinity of mitoxantrone to the allosteric site. These findings introduce a combination therapy approach that potentially restores MRSA's susceptibility to β-lactam antibiotics.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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