Development of customized aluminosilicates as complementary topical therapeutics for wound infections

开发定制的硅铝酸盐作为伤口感染的补充局部治疗剂

• 批准号: 9180581
• 负责人: SHELLEY E HAYDEL
• 金额: $ 21.1万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180581
• 关键词: AIDS/HIV problem; Address; Adsorption; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Toxins; Binding Proteins; Buruli Ulcer; Cells; Cessation of life; Characteristics; Charge; Chemicals; Copper; Country; Cutaneous; Debridement; Development; Divalent Cations; Effectiveness; Ensure; Enzymes; Epithelial Cells; Excision; Exhibits; Exotoxins; Exudate; Fibroblasts; Fostering; Goals; Healed; Health; Healthcare; Hemolysin; Homicide; Human; Hydrophobicity; Immunotherapy; In Vitro; Individual; Infection; Infectious Agent; Infectious Skin Diseases; Investigation; Ion Exchange; Ions; Iron; Kinetics; Licensing; Mediating; Medicine; Metals; Microbial Biofilms; Mission; Mycobacterium ulcerans; Necrosis; Nodule; Operative Surgical Procedures; Oral; Organism; Parkinson Disease; Pathology; Patients; Play; Polymers; Prevention; Process; Property; Proteins; Public Health; Pulmonary Emphysema; Recurrence; Research; Resistance development; Resistance to infection; Resources; Role; Safety; Skin; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus; Sterile coverings; Structure; Surface; Surface Properties; Technology; Therapeutic; Topical application; Toxin; Ulcer; United States National Institutes of Health; Variant; Virulence; Wound Healing; Wound Infection; Zeolites; absorption; aluminosilicate; bactericide; base; combat; cost; cytotoxic; cytotoxicity; design; diabetic; drug candidate; experience; extracellular; healing; human disease; hydrophilicity; improved; in vivo; innovation; killings; macrophage; methicillin resistant Staphylococcus aureus; mycolactone; nanosized; nanostructured; neglected tropical diseases; novel; novel therapeutics; parenteral administration; pre-clinical; prevent; prophylactic; skin disorder; skin lesion; soft tissue; therapeutic vaccine; tissue repair; treatment planning; wound

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.

项目摘要 抗菌素耐药性是全世界对人类健康的最大威胁之一。只是一个生物， 耐甲氧西林金黄色葡萄球菌（MRSA）杀死美国公民多于艾滋病毒/艾滋病，肺气肿， 帕金森氏病和杀人剂结合在一起。而治疗或预防抗生素耐药的新策略 感染处于医疗森林方面 也非常需要热带疾病，例如Buruli溃疡。多达100,000人死亡和成本 $ 3.5B每年与伤口感染有关。在管道中缺乏新毒品的候选者和 细菌快速发展对狭窄和广谱抗生素的抗性的能力，我们正在探索 打击皮细菌感染的互补和综合策略。我们以前有 证明铁和铜金属离子介导了与天然有关的体外抗菌活性 粘土。但是，由于天然粘土的巨大抗菌和化学变异性，化学的控制 铝硅酸盐的结构和表面特性对于生物医学应用是必需的。电流 提案专门旨在开发浸渍的层次结构，纳米化和纳米结构的沸石 Ag+，Cu2+或Fe2+金属离子介导抗菌离子的局部递送。这些离子交换 纳米唑石将合成并检查针对MRSA和分枝杆菌的细菌潜力 溃疡的妇女溃疡的病因，可破坏MRSA生物膜和细胞毒性的能力 针对巨噬细胞，成纤维细胞和上皮细胞。除了纳米唑介导的局部释放 活性杀菌离子，我们将开发经过修饰的多孔地聚合物以在表面表现出变化 疏水性，亲水性和电荷。这些表面修饰的地聚合物将进行研究 吸附细菌（MRSA和M. ulcerans），细菌蛋白和特异性毒素的能力 细菌。我们假设表面修饰的地球聚合物将吸附细菌，毒素和渗出液 在受感染的伤口内，通过敷料变化和非手术吸附剂介导身体去除 清创术。这些研究将提供重要的临床前结果，旨在优化体内材料 对伤口闭合和愈合的有效性和有益影响。拟议的研究与NIH有关 旨在通过促进与事业相关的基本发现来改善人类健康的任务 预防，治愈人类疾病，并为国家努力确保稳定的新有效 对抗传染性药物的治疗策略。