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Abstract：
The threat of methicillin-resistant Staphylococcus aureus (MRSA) is increasing worldwide, making it significantly necessary to discover a novel way of dealing with related infections. The quick spread of MRSA isolates among infected individuals has heightened public health concerns and significantly limited treatment options. Vancomycin (VAN) can be applied to treat severe MRSA infections, and the indiscriminate administration of this antimicrobial agent has caused several concerns in medical settings. Owing to several advantageous characteristics, a niosomal drug delivery system may increase the potential of loaded antimicrobial agents. This work aims to examine the antibacterial and anti-biofilm properties of VAN-niosome against MRSA clinical isolates with emphasis on cytotoxicity and stability studies. Furthermore, we aim to suggest an effective approach against MRSA infections by investigating the inhibitory effect of formulated niosome on the expression of the biofilm-associated gene (icaR). The thin-film hydration approach was used to prepare the niosome (Tween 60, Span 60, and cholesterol), and field emission scanning electron microscopy (FE-SEM), an in vitro drug release, dynamic light scattering (DLS), and entrapment efficiency (EE%) were used to investigate the physicochemical properties. The physical stability of VAN-niosome, including hydrodynamic size, polydispersity index (PDI), and EE%, was analyzed for a 30-day storage time at 4 °C and 25 °C. In addition, the human foreskin fibroblast (HFF) cell line was used to evaluate the cytotoxic effect of synthesized niosome. Moreover, minimum inhibitory and bactericidal concentrations (MICs/MBCs) were applied to assess the antibacterial properties of niosomal VAN formulation. Also, the antibiofilm potential of VAN-niosome was investigated by microtiter plate (MTP) and real-time PCR methods. The FE-SEM result revealed that synthesized VAN-niosome had a spherical morphology. The hydrodynamic size and PDI of VAN-niosome reported by the DLS method were 201.2 nm and 0.301, respectively. Also, the surface zeta charge of the prepared niosome was - 35.4 mV, and the EE% ranged between 58.9 and 62.5%. Moreover, in vitro release study revealed a sustained-release profile for synthesized niosomal formulation. Our study showed that VAN-niosome had acceptable stability during a 30-day storage time. Additionally, the VAN-niosome had stronger antibacterial and anti-biofilm properties against MRSA clinical isolates compared with free VAN. In conclusion, the result of our study demonstrated that niosomal VAN could be promising as a successful drug delivery system due to sustained drug release, negligible toxicity, and high encapsulation capacity. Also, the antibacterial and anti-biofilm studies showed the high capacity of VAN-niosome against MRSA clinical isolates. Furthermore, the results of real-time PCR exhibited that VAN-niosome could be proposed as a powerful strategy against MRSA biofilm via down-regulation of icaR gene expression.
摘要：
耐甲氧西林金黄色葡萄球菌（MRSA）在全球范围内的威胁正在增加，这使得有必要发现一种处理相关感染的新方法。MRSA分离株在受感染个体中的快速传播加剧了公共卫生问题，并极大地限制了治疗选择。万古霉素（VAN）可用于治疗严重的MRSA感染，这种抗微生物剂的滥用在医疗环境中引起了一些关注。由于几个有利的特点，脂质体给药系统可能增加负载的抗微生物剂的潜力。这项工作旨在研究VAN-niosome对MRSA临床分离株的抗菌和抗生物膜特性，重点是细胞毒性和稳定性研究。此外，我们旨在通过研究配制的niosome对生物膜相关基因（icaR）表达的抑制作用，提出一种有效的方法来对抗MRSA感染。薄膜水合方法用于制备niosome（Tween60，Span60和胆固醇），场发射扫描电子显微镜（FE-SEM），体外药物释放，动态光散射(DLS),和包封率(EE%)用于研究理化性质。VAN-niosome的物理稳定性，包括流体动力学尺寸，多分散指数(PDI)，和EE%，在4°C和25°C下分析30天的储存时间。此外,人包皮成纤维细胞（HFF）细胞系用于评估合成的脂质体的细胞毒性作用。此外，应用最小抑制和杀菌浓度(MIC/MBC)评估脂质体VAN制剂的抗菌性能.此外，通过微量滴定板（MTP）和实时PCR方法研究了VAN-niosome的抗生物膜潜力。FE-SEM结果表明，合成的VAN脂质体具有球形形态。通过DLS方法报告的VAN-niosome的流体动力学尺寸和PDI分别为201.2nm和0.301。此外，制备的脂质体的表面zeta电荷为-35.4mV，EE%介于58.9％和62.5％之间。此外，体外释放研究显示，合成的脂质体制剂具有缓释特性。我们的研究表明，VAN-niosome在30天的储存时间内具有可接受的稳定性。此外,与游离VAN相比,VAN-niosome对MRSA临床分离株具有更强的抗菌和抗生物膜特性.总之,我们的研究结果表明，由于持续的药物释放，NiosomalVAN可能是一种成功的药物递送系统，可忽略的毒性，和高封装能力。此外，抗菌和抗生物膜研究表明,VAN-niosome对MRSA临床分离株具有很高的抗菌能力.此外，实时PCR结果表明，VAN-niosome可以通过下调icaR基因表达来作为对抗MRSA生物膜的有力策略。
