Glycosylated Atomically-Precise Gold Clusters: Design, Synthesis and Antimicrobial Activity

糖基化原子精确金簇：设计、合成和抗菌活性

• 批准号: 9585513
• 负责人: MINGDI YAN
• 金额: $ 18.97万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-02 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9585513
• 关键词: Address; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antirheumatic Agents; Auranofin; Bacteria; Biochemistry; Carbohydrates; Cell Death; Cell membrane; Cells; Cellular Morphology; Cellular biology; Cessation of life; Chemistry; Complex; Dose; Family; Generations; Goals; Gold; Gram-Negative Bacteria; Health Care Costs; Healthcare; Human; In Vitro; Infection; Investigation; Ions; Knowledge; Ligands; Livestock; Membrane; Metals; Microbiology; Minimum Inhibitory Concentration measurement; Morbidity - disease rate; NMR Spectroscopy; Outcome; Pathogenicity; Pharmaceutical Preparations; Phosphines; Physiological; Prevalence; Production; Proteins; Public Health; Resistance; Resistance development; Rheumatoid Arthritis; Risk; Source; Work; antimicrobial; antimicrobial drug; arm; bacterial resistance; base; carbohydrate structure; clinically relevant; combat; cytotoxicity; design; global health; glycosylation; innovation; microorganism; mortality; nanocarrier; nanocluster; novel therapeutics; oxidation; receptor; tool; uptake

Project Summary The increasing prevalence of antimicrobial resistance (AMR) to the majority of existing antibiotics has generated a pressing global healthcare crisis. Certain highly resistant bacteria have acquired multiple mechanisms against all available antibiotics. New therapeutic formats that can overcome AMR are therefore in urgent need, and detailed understanding of their action is essential to combat bacterial resistance. Certain metal ions, such as AuI is known to be toxic to bacteria. Recent studies have shown that auranofin, a AuI-based drug against rheumatoid arthritis, displays potent antibacterial activity. If large amounts of AuI can be delivered to bacteria in a sustained manner, selectively driven by interactions with bacterial receptors, this would greatly enhance the antimicrobial efficacy owing to the increased and prolong local concentration AuI at or within the microorganisms. Consequently, the overall objective of this project is to develop and explore new antimicrobial agents, designed to result in targeted generation of AuI for bacterial cell death. We hypothesize that glycosylated and phosphine-coordinated, atomically-precise gold nanoclusters (AuNCs) can be selectively and multivalently addressed to specific bacteria, and thereby release large quantities of AuI at or within the cells for efficient antibacterial action. We also hypothesize that a judicial choice of phosphine coordination to the AuNCs can fine-tune the stability of the clusters, whereby a controlled and sustained AuI release can be achieved. The approach is innovative because glycosylated, atomically-precise gold nanoclusters represent a new class of antimicrobial agents through specific and multivalent bacterial targeting, and sustained release. The project is significant because it represents a new way to overcome AMR, and the work will contribute our fundamental understanding regarding the antimicrobial action of ultrasmall gold clusters. In Aim 1 of this project, we will synthesize atomically-precise gold clusters, functionalized with specific carbohydrate structures for selective targeting to bacteria. We anticipate that ultrasmall, well-defined, glycosylated AuNCs can serve as metastable delivery vehicles for antimicrobial AuI ions, through controlled disintegration and oxidation at or within bacterial cells. In Aim 2, the activity and antimicrobial mechanism of the glycosylated AuNCs will be studied with all classes of bacteria.

项目摘要 对大多数现有抗生素的抗菌素耐药性（AMR）的日益普遍， 紧迫的全球医疗危机。某些高度耐药的细菌已经获得了多种机制， 所有可用的抗生素因此，迫切需要能够克服AMR的新的治疗形式， 详细了解它们的作用对于对抗细菌耐药性至关重要。 某些金属离子，如AuI，已知对细菌有毒。最近的研究表明，金诺芬， 基于Au I的抗类风湿性关节炎药物，显示出有效的抗菌活性。如果大量的AuI可以 通过与细菌受体的相互作用选择性地以持续的方式传递给细菌，这将 由于局部浓度的增加和延长， 微生物。因此，本项目的总体目标是开发和探索新的 抗微生物剂，旨在导致靶向产生AuI用于细菌细胞死亡。我们假设 糖基化和膦配位的原子精确的金纳米团簇（AuNC）可以选择性地 并多价地针对特定细菌，从而在细胞处或细胞内释放大量AuI 有效的抗菌作用。我们还假设，一个司法选择的膦协调，以 AuNC可以微调簇的稳定性，从而可以控制和持续释放AuI。 办妥了一批这种方法是创新的，因为糖基化的，原子精确的金纳米团簇代表了一种 通过特异性和多价细菌靶向作用和持续释放的新型抗微生物剂。 该项目意义重大，因为它代表了克服AMR的新方法，这项工作将有助于我们的 关于超小金簇的抗菌作用的基本理解。 在本项目的目标1中，我们将合成原子精确的金簇，用特定的 碳水化合物结构，用于选择性靶向细菌。我们预计，超小，明确， 糖基化的AuNCs可以作为抗菌AuI离子的亚稳态传递载体，通过控制 在细菌细胞处或细菌细胞内的分解和氧化。在目的2中，研究了该化合物的活性和抗微生物机制。 将用所有种类的细菌研究糖基化AuNC。