School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, China.
School of Food Science, Henan Institute of Science and Technology, Xinxiang, China.
Biomaterials. 2022 Nov;290:121842. doi: 10.1016/j.biomaterials.2022.121842. Epub 2022 Sep 30.
Hydrogels loaded with ampicillin, vancomycin or other antibiotics are one of the most widely used therapeutic agents for keratitis caused by Staphylococcus aureus. However, emergence of methicillin-resistant S. aureus (MRSA) makes infections harder to be treated by antibiotic-based hydrogels, urging the development of novel antibacterial materials. Inspired by mammalian ferroptosis, we determined the bactericidal effects of ferrous sulfate (FeSO) on S. aureus, and evaluated the therapeutic potential of FeSO-loaded hydrogel in a mouse keratitis model. The results showed that FeSO facilitated ferroptosis-like cell death in S. aureus with the key characteristics of reactive oxygen species (ROS) generation and lipid peroxidation. Notably, FeSO also efficiently killed persisters and MRSA, and eliminated biofilms of S. aureus. RNA profiles demonstrated that ferroptosis-related genes were significantly up-regulated, and the genes responsible for cell wall and cell membrane biosynthesis were down-regulated after exposure to Fe, supporting the occurrence of ferroptosis and cell lysis. We further prepared a FeSO-loaded hydrogel by using hyaluronic acid (HA) and ascorbate. The FeSO hydrogel has the characteristics of injectability, self-healing, uniform distribution of Fe in the three-dimensional gel structure, appropriate fluidity, high-water retention, high efficacy to kill MRSA, and excellent biocompatibility. In a mouse keratitis model, we showed that treatment of animals with FeSO hydrogel led to a rapid recovery of from keratitis, prevented the dissimilation of MRSA to the lung, and alleviated systemic inflammation, demonstrating the therapeutic potential of FeSO hydrogel. Taken together, our results indicated that FeSO hydrogel is a promising alternative to current antibiotics-dependent therapeutic materials for the treatment of infections by MRSA.
载有氨苄西林、万古霉素或其他抗生素的水凝胶是治疗金黄色葡萄球菌引起的角膜炎最广泛使用的治疗剂之一。然而，耐甲氧西林金黄色葡萄球菌（MRSA）的出现使得基于抗生素的水凝胶更难治疗感染，这促使人们开发新型抗菌材料。受哺乳动物铁死亡的启发，我们确定了硫酸亚铁（FeSO）对金黄色葡萄球菌的杀菌作用，并在小鼠角膜炎模型中评估了载有 FeSO 的水凝胶的治疗潜力。结果表明，FeSO 促进了金黄色葡萄球菌发生类似于铁死亡的细胞死亡，其具有活性氧（ROS）生成和脂质过氧化的关键特征。值得注意的是，FeSO 还能有效杀死持久性细菌和 MRSA，并消除金黄色葡萄球菌的生物膜。RNA 谱表明，铁死亡相关基因显著上调，而与细胞壁和细胞膜生物合成相关的基因下调，这支持了铁死亡和细胞裂解的发生。我们进一步使用透明质酸（HA）和抗坏血酸制备了载有 FeSO 的水凝胶。FeSO 水凝胶具有可注射性、自修复性、三维凝胶结构中 Fe 分布均匀、流动性适中、高保水性、高效杀灭 MRSA 和良好的生物相容性等特点。在小鼠角膜炎模型中，我们表明用 FeSO 水凝胶治疗动物可迅速从角膜炎中恢复，防止 MRSA 向肺部分化，并缓解全身炎症，证明了 FeSO 水凝胶的治疗潜力。总之，我们的研究结果表明，FeSO 水凝胶是治疗耐甲氧西林金黄色葡萄球菌感染的现有抗生素依赖性治疗材料的一种有前途的替代方法。
