Indigenous Free Fatty Oleic acid Against MRSA Skin Infection

本土游离脂肪油酸对抗 MRSA 皮肤感染

• 批准号: 7991210
• 负责人: CHUN-MING HUANG
• 金额: $ 25.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-07 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991210
• 关键词: Accounting; Adverse effects; Antibiotic Resistance; Antibiotics; Area; Back; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Binding; Biological; Cell Line; Cell Wall; Cessation of life; Characteristics; Cloxacillin; Communities; Community-Acquired Infections; Data; Defensins; Development; Disease; Disease Outbreaks; Drug resistance; Engineering; Enhancers; Equilibrium; Exhibits; Figs - dietary; Floxacillin; Future; Generations; Gram-Positive Bacteria; Growth; Hospitalization; Hospitals; Human; Hydrophobicity; Immune response; In Vitro; Indigenous; Infection; Infectious Skin Diseases; Interleukin-1 beta; Lipids; Liposomes; Medicine; Methicillin; Monoclonal Antibodies; Mus; Nanotechnology; Natural Immunity; Nonesterified Fatty Acids; Nosocomial Infections; Oleic Acids; Organ; Organ failure; Outpatients; Patients; Persons; Pharmaceutical Preparations; Property; Reporting; Research; Research Personnel; Resistance; Risk; Role; Severities; Shapes; Skin; Solid; Staphylococcus aureus; Surface; Systemic infection; Therapeutic; Vascular Endothelial Growth Factors; Virulence Factors; Visit; Wild Type Mouse; Work; antibody conjugate; antimicrobial; bactericide; base; fighting; killings; methicillin resistant Staphylococcus aureus; microbiome; mouse model; mutant; nano; nanosized; novel strategies; novel therapeutics; pathogen; pressure; public health relevance; resistance mechanism; resistant strain; skin lesion; soft tissue; stem; water solubility; wound

DESCRIPTION (provided by applicant): The central aim of this proposal is to explore the anti-Staphylococcus aureus (S. aureus) activity of endogenous oleic acid (OA), a monounsaturated omega-9 free fatty acid (FFA) naturally existed in humans. The S. aureus bacteria, in particular, methicillin-resistant S. aureus (MRSA), are pathogenic and have a number of virulence factors that enable them to result in disease. They are transmissible and important causes of nosocomial infections worldwide. An MRSA outbreak can occur when one strain is transmitted to other patients or through close contacts of infected persons in the community. Our preliminary results indicated that OA is a biological molecule with bifunctionality: killing MRSA bacteria and enhancing host innate immunity. Here we propose three Specific Aims to (a) investigate the role of endogenous FFA in bacterial killing and host responses to FFA exposures; and (b) develop an FFA-derived new therapeutic against S. aureus/MRSA skin infections. Three Specific Aims are to (1) Examine the S. aureus strain selectivity of FFAs and investigate the anti-Staphylococcal activity of endogenous FFAs using FFAs-deficient mice; (2) Engineer a Nano-liposome-based FFA (Nano- LipoFFA) specifically targeting S. aureus and explore the bactericidal mechanism of Nano-LipoFFA via physicochemical analysis; and (3) Evaluate the potency of targeted Nano-LipoFFA against S. aureus skin infections and assess the host response to targeted Nano-LipoFFA. To carry out the proposed research, we have formed a solid research team consisting of two bacteriologists (Dr. Chun-Ming Huang, PI; Dr. Richard Gallo, co-investigator), a S. aureus expert (Dr. Victor Nizet, consultant), two nanotechnology engineers (Dr. Mirianas Chachisvilis, co-investigator and Dr. Liangfang Zhang, consultant), and a lipid biologist (Dr. Alan F. Hofmann, consultant). When successful, the results from this proposal will have broad impacts because (a) uncovering the role of endogenous free fatty acids in innate immunity will open a new area of research on host-pathogen interaction; (b) this work may provide a brand new approach to treat MRSA and S. aureus related infections, thereby benefiting the entire community of patients with MRSA infections consisting of over 126,000 patients per year in US; and (c) a similar strategy may potentially be used to treat various infections or diseases caused by other bacteria, thereby benefiting a larger patient community. PUBLIC HEALTH RELEVANCE: S. aureus infection on skin and soft tissue comprises more than 75% of MRSA disease. Treatment of S. aureus/MRSA skin infection using an endogenous oleic acid will be in compliance with evolutionary medicine since the endogenous compound causes a lower risk of developing new drug-resistant S. aureus strains and may have less side effects to patients.

描述（由申请人提供）： 本研究的主要目的是探索抗金黄色葡萄球菌（S。金黄色葡萄球菌）的内源性油酸（OA）（一种天然存在于人体中的单不饱和ω-9游离脂肪酸（FFA））活性。色葡萄金黄色葡萄球菌，特别是耐甲氧西林的S.金黄色葡萄球菌（MRSA）是致病性的，并且具有使它们能够导致疾病的许多毒力因子。它们是全球范围内医院感染的传播性和重要原因。当一种菌株传播给其他患者或通过社区中受感染者的密切接触者时，可能发生MRSA爆发。我们的初步结果表明OA是一种具有双重功能的生物分子：杀死MRSA细菌和增强宿主的先天免疫。在这里，我们提出了三个具体目标：（a）研究内源性FFA在细菌杀伤和宿主对FFA暴露的反应中的作用;（B）开发一种源自FFA的抗链球菌新治疗方法。金黄色葡萄球菌/MRSA皮肤感染。三个具体的目的是：（1）检查S。金黄色葡萄球菌菌株的FFA选择性，并使用FFA缺陷小鼠研究内源性FFA的抗葡萄球菌活性;（2）设计特异性靶向S.通过理化分析探讨Nano-LipoFFA的杀菌机理;（3）评价靶向Nano-LipoFFA对金黄色葡萄球菌的杀菌效力。金黄色葡萄球菌皮肤感染，并评估宿主对靶向Nano-LipoFFA的反应。为了开展这项研究，我们组建了一个坚实的研究团队，包括两名细菌学家（黄春明博士，PI;理查德加洛博士，共同研究者），一名S。金黄色葡萄球菌专家（维克托Nizet博士，顾问），两名纳米技术工程师（Mirianas Chachisvilis博士，共同研究者和Liangfang Zhang博士，顾问）和脂质生物学家（Alan F. Hofmann，consultant）.一旦成功，这项提议的结果将产生广泛的影响，因为（a）揭示内源性游离脂肪酸在先天免疫中的作用将开辟宿主-病原体相互作用的新研究领域;（B）这项工作可能提供一种全新的治疗MRSA和S.金黄色葡萄球菌相关的感染，从而使美国每年超过126，000名患者的MRSA感染患者的整个社区受益;以及（c）类似的策略可以潜在地用于治疗由其他细菌引起的各种感染或疾病，从而使更大的患者社区受益。 公共卫生关系： S.皮肤和软组织上的金黄色葡萄球菌感染包括超过75%的MRSA疾病。治疗S.使用内源性油酸治疗金黄色葡萄球菌/MRSA皮肤感染将符合进化医学，因为内源性化合物导致产生新的耐药金黄色葡萄球菌的风险较低。金黄色葡萄球菌菌株，可能对患者的副作用较小。