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 抗生素耐药性是全球人类健康面临的最大威胁之一。只有一个有机体， 耐甲氧西林金黄色葡萄球菌（MRSA），杀死更多的美国公民比艾滋病毒/艾滋病，肺气肿， 帕金森综合症和谋杀。虽然治疗或预防抗药性的新策略 感染是医疗保健的前沿，治疗顽固性或复发性伤口感染， 还非常需要预防热带疾病，如布鲁里溃疡。多达10万人死亡， 每年有35亿美元与伤口感染有关。由于缺乏新的候选药物， 细菌对窄谱和广谱抗生素迅速产生耐药性的能力，我们正在探索 补充和综合策略，以对抗皮肤细菌感染。我们先前已经 证明铁和铜金属离子介导与天然抗菌剂相关的体外抗菌活性， 粘土。然而，由于天然粘土的巨大的抗菌性和化学可变性， 硅铝酸盐的结构和表面性质对于生物医学应用是必需的。当前 一项提案特别旨在开发浸渍有以下物质的分级、纳米尺寸和纳米结构的沸石： Ag+、Cu 2+或Fe 2+金属离子介导抗菌离子的局部递送。这些离子交换 将合成纳米沸石，并检测其对MRSA和分枝杆菌的杀菌潜力 溃疡，布鲁里溃疡的病原体，破坏MRSA生物膜的能力和细胞毒性 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外， 活性杀菌离子，我们将开发多孔地质聚合物改性，以表现出不同的表面 疏水性、亲水性和电荷。这些表面改性的地质聚合物将被研究， 吸附细菌（MRSA和M.溃疡）、细菌蛋白和由这些分泌的特定毒素 细菌我们假设表面改性的地质聚合物会吸附细菌、毒素和渗出物 在感染的伤口内，并通过敷料更换和非手术吸附 清创术这些研究将提供重要的临床前结果，旨在优化材料， 对伤口闭合和愈合的功效和有益效果。这项研究与美国国立卫生研究院有关。 使命旨在通过促进与该事业相关的基本发现来改善人类健康， 预防和治疗人类疾病以及国家努力，确保新的和有效的 治疗策略来对抗传染性病原体。