Development of customized aluminosilicates as complementary topical therapeutics for wound infections

项目总结 抗菌素耐药性是全世界对人类健康的最大威胁之一。只有一种有机体， 耐甲氧西林金黄色葡萄球菌(MRSA)导致的美国公民死亡人数超过艾滋病毒/艾滋病、肺气肿、 帕金森氏症和凶杀案加在一起。虽然治疗或预防抗生素耐药性的新策略 感染处于医疗保健的前沿，治疗顽固性或复发的伤口感染而被忽视 热带病，如布鲁里溃疡，也是非常需要的。多达10万人的死亡和损失 每年有35亿美元与伤口感染有关。在缺乏新的候选药物的情况下 细菌对窄谱和广谱抗生素迅速产生抗药性的能力，我们正在探索 对抗皮肤细菌感染的互补和综合战略。我们之前已经 铁和铜金属离子介导的体外抗菌活性与天然 粘土。然而，由于天然粘土的巨大抗菌性和化学变异性，控制化学物质， 铝硅酸盐的结构和表面性质对于生物医学应用是必要的。海流 该提案特别旨在开发分级、纳米尺寸和纳米结构的沸石分子筛，其中 Ag、Cu2或Fe2金属离子，以介导抗菌离子的局部传递。这些离子交换 将合成纳米沸石，并检测其对耐甲氧西林金黄色葡萄球菌和分枝杆菌的杀菌潜力 溃疡，布鲁里溃疡的病原体，破坏MRSA生物膜的能力，以及细胞毒性 抗巨噬细胞、成纤维细胞和上皮细胞。除了纳米沸石介导的局部释放 活性杀菌离子，我们将开发经修饰的多孔地球聚合物，以显示表面的变化 疏水性、亲水性和电荷。这些表面改性的地球聚合物将被研究用于 能够吸附细菌(MRSA和溃烂分枝杆菌)、细菌蛋白和由这些细菌分泌的特定毒素 细菌。我们推测，表面修饰的地球聚合物将会吸附细菌、毒素和渗出物。 在感染伤口内，通过换药和非手术吸附来中介物理移除 清创手术。这些研究将提供重要的临床前研究结果，旨在优化体内材料 在伤口闭合和愈合方面的功效和有益效果。这项拟议的研究与美国国立卫生研究院有关 旨在通过促进与这一事业相关的基本发现来改善人类健康的任务， 预防和治疗人类疾病以及国家努力确保稳定的新的有效的管道 对抗感染性病原体的治疗策略。

PROJECT SUMMARY Antimicrobial resistance is one of the greatest threats to human health worldwide. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more U.S. citizens than HIV/AIDS, emphysema, Parkinson’s disease, and homicide combined. While new strategies to treat or prevent antibiotic-resistant infections are at the healthcare forefront, treatment for recalcitrant or recurring wound infections and neglected tropical diseases, such as Buruli ulcer, are also greatly needed. As many as 100,000 deaths and costs of $3.5B annually are associated with wound infections. With a lack of new drug candidates in the pipeline and the ability of bacteria to rapidly develop resistance to narrow and broad-spectrum antibiotics, we are exploring complementary and integrative strategies to combat cutaneous bacterial infections. We have previously demonstrated that iron and copper metal ions mediate in vitro antibacterial activity associated with natural clays. However, due to vast antibacterial and chemical variability of natural clays, control of chemical, structural, and surface properties of aluminosilicates is necessary for biomedical applications. The current proposal specifically aims to develop hierarchical, nanosized, and nanostructured zeolites impregnated with Ag+, Cu2+, or Fe2+ metal ions to mediate localized delivery of antibacterial ions. These ion-exchanged nanozeolites will be synthesized and examined for bactericidal potential against MRSA and Mycobacterium ulcerans, the causative agent of Buruli ulcer, for the ability to disrupt MRSA biofilms, and for cytotoxicity against macrophages, fibroblasts, and epithelial cells. In addition to nanozeolite-mediated localized release of active bactericidal ions, we will develop porous geopolymers modified to exhibit variations in surface hydrophobicity, hydrophilicity, and charge. These surface-modified geopolymers will be investigated for the ability to adsorb bacteria (MRSA and M. ulcerans), bacterial proteins, and specific toxins secreted by these bacteria. We hypothesize that the surface-modified geopolymers will adsorb bacteria, toxins, and exudate within infected wounds and mediate physical removal via dressing changes and non-surgical adsorptive debridement. These studies will provide important preclinical results designed to optimize materials for in vivo efficacy and beneficial effects on wound closure and healing. The proposed research is relevant to the NIH mission designed to improve human health by fostering fundamental discoveries related to the cause, prevention, and cure of human diseases and to national efforts ensuring a steady pipeline of new and effective therapeutic strategies to combat infectious agents.