Robust Delivery of Antimicrobial Peptides

抗菌肽的强力递送

• 批准号: 10187520
• 负责人: DOUGLAS G HAYES
• 金额: $ 6.59万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187520
• 关键词: Address; Adsorption; Alternative Therapies; Antibiotic Resistance; Bacteria; Biocompatible Materials; Biological; Biological Assay; Biological Sciences; Biomedical Engineering; Cells; Charge; Chlorhexidine; Chronic; Circular Dichroism; Clinical; Development; Devices; Drug Delivery Systems; Drug Stability; Encapsulated; Enhancers; Epidemiology; Equipment; Eukaryota; Extravasation; Future; Health Care Costs; Healthcare; Hemolysis; Homologous Gene; Hospitalization; Hydrophobicity; Infection; Liquid substance; Local Anti-Infective Agents; Measurement; Measures; Medical; Medical Device; Membrane; Methods; Mission; National Institute of Allergy and Infectious Disease; National Institute of Biomedical Imaging and Bioengineering; Neutrons; Oils; Operative Surgical Procedures; Optics; Penetration; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Preparation; Property; Proteolysis; Radiolabeled; Research; Resistance development; Risk; Site; Structure; Surface; System; Technology; Testing; Thermodynamics; Topical Preparation; Topical application; United States National Institutes of Health; Water; Wound Infection; amphiphilicity; anti-cancer; antimicrobial; antimicrobial drug; antimicrobial peptide; bactericide; base; bioimaging; biomaterial compatibility; chronic wound; clinical application; combat; cost; cytotoxicity; diabetic ulcer; experience; experimental study; fluidity; hydrophilicity; improved; interfacial; methicillin resistant Staphylococcus aureus; microorganism; mimetics; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; pathogenic microbe; prevent; programs; receptor; research and development; societal costs; surfactant; wound; wound treatment

Project Summary This project explores the development of bicontinuous microemulsions (BEs) as topical drug delivery systems for antimicrobial peptides (AMPs), as an alternative therapy to treat wound infections. This study addresses the missions of both the NIH’s NIBIB and NIAID research programs through: 1) the development of a novel drug delivery technology, and 2) a new approach to combat chronic wound infections exacerbated by antibiotic-resistant microorganisms. Wound infections are a major problem due to the increased occurrence of antibiotic-resistant microorganisms, which are attributable to $20 billion annually in excess health care costs, $35 billion in societal costs, and 8 million days of extended hospitalization stays in the US. AMPs can kill microbial pathogens that cause wound infections (e.g., methicillin-resistant Staphylococcus aureus [MRSA]) through disruption of negatively charged biomembranes, producing pores that allow leakage of cytoplasmic fluids; however, AMPs must be delivered in a highly folded form to be effective and previous studies have not addressed this need. Thus, this study proposes to develop BEs as systems for encapsulation of AMPs in their folded state and delivery to wound surfaces. BEs are optically clear, homogeneous, and thermodynamically stable biomembrane mimetic systems. They possess unique drug-delivery properties compared to other membrane-based systems, including large-volume fractions of water and oil (~40%) that allow co-solubilization of other drugs. Preliminary studies demonstrate that the AMP melittin when encapsulated into BEs can reside in a highly folded state (>90% -helix) and high concentrations (1-10 g/L) are achievable. Several important hypotheses will be tested, including that AMP-loaded BE solutions are effective antimicrobial agents with activity strongly controlled by the extent of AMP folding. The Specific Aims are to 1) demonstrate that four diverse AMPs can be incorporated into several different biocompatible BE systems at high (biologically relevant) concentrations and degrees of folding; 2) show that BEs loaded with AMPs and antiseptic agents such as chlorhexidine (derived in Aim 1) can serve as robust topical preparations for treatment of wound infections. For Aim 1, the relationship between AMP folding and BE properties will be determined through novel methods, including circular dichroism and small-angle neutron scattering. Aim 2 will provide measurements of minimum inhibitory and bactericidal concentration against several representative microorganisms encountered in wounds (including MRSA), cell cytotoxicity (hemolysis) activity and protection of BE-encapsulated AMPs from proteolysis. The results will provide a basis for future clinical applications to use BEs as a drug delivery system for improved activity and/or stability of cell-penetrating peptides. Other applications include adsorption to surfaces of medical devices for antimicrobial coatings and delivery of radiolabeled AMPs for bioimaging.

项目摘要 本项目探讨了双连续微乳作为局部给药系统的发展 抗菌肽（AMP），作为治疗伤口感染的替代疗法。这项研究涉及的 NIH的NIBIB和NIAID研究计划的任务是：1）开发一种新药 输送技术，以及2）一种对抗慢性伤口感染的新方法，这种感染因 耐药性微生物伤口感染是一个主要的问题，由于增加的发生率， 抗药性微生物每年造成200亿美元的超额医疗费用， 350亿美元的社会成本，以及美国800万天的延长住院时间。AMP可以杀死 引起伤口感染的微生物病原体（例如，耐甲氧西林金黄色葡萄球菌（MRSA）） 通过破坏带负电荷的生物膜，产生允许细胞质渗漏的孔， 然而，AMP必须以高度折叠的形式递送才能有效，而先前的研究还没有 满足了这一需求。因此，本研究提出开发B微囊化酶作为用于将AMP包封在其微囊化酶中的系统。 折叠状态和递送到伤口表面。B类光致发光材料是光学透明的、均匀的、且在光学上是透明的。 稳定的生物膜模拟系统。与其他药物相比，它们具有独特的药物递送特性。 基于膜的系统，包括允许共溶解的大体积分数的水和油（~40%） 其他药物。初步研究表明，AMP蜂毒素包封在B囊泡中时， 在高度折叠状态下（> 90% β-螺旋）和高浓度（1 - 10 g/L）是可实现的。几个重要 将对假设进行检验，包括AMP负载的B C1E溶液是有效的抗微生物剂， 活性受AMP折叠程度的强烈控制。具体目标是：（1）证明四个 不同的AMP可以在高（生物学上）浓度下掺入到几种不同的生物相容性B EAE系统中 相关）浓度和折叠程度; 2）显示负载AMP和防腐剂的B酶 例如氯己定（来源于目标1）可以用作治疗伤口的稳健的局部制剂 感染.对于目标1，AMP折叠和B EAE性质之间的关系将通过以下公式确定： 新的方法，包括圆二色性和小角中子散射。目标2将提供 对几种代表性菌株的最低抑菌浓度和杀菌浓度的测定 伤口中遇到的微生物（包括MRSA）、细胞毒性（溶血）活性和保护 来自蛋白水解的B β-环糊精包封的AMP。该结果将为未来的临床应用提供基础， 使用B-β-环糊精作为药物递送系统，用于改善细胞穿透肽的活性和/或稳定性。其他 应用包括吸附到医疗装置的表面用于抗菌涂层和递送抗菌剂。 放射性标记的AMP用于生物成像。

项目成果

Assessment of antimicrobial activity of melittin encapsulated in bicontinuous microemulsions prepared using renewable oils.

评估使用可再生油制备的双连续微乳液中封装的蜂毒肽的抗菌活性。

• DOI: 10.1002/jsde.12654
• 发表时间: 2023
• 期刊: Journal of surfactants and detergents
• 影响因子: 1.6
• 作者: Oehler,MadisonA;Hayes,DouglasG;D'Souza,DorisH;Senanayake,Manjula;Gurumoorthy,Viswanathan;Pingali,SaiVenkatesh;O'Neill,HughM;Bras,Wim;Urban,VolkerS
• 通讯作者: Urban,VolkerS