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）： 该提议的核心目的是探索内源性油酸（OA）的抗稳定金黄色葡萄球菌（Aureus）活性，这是人类中自然存在的单不饱和omega-9自由脂肪酸（FFA）。金黄色葡萄球菌，尤其是耐甲氧西林金黄色葡萄球菌（MRSA）是致病性的，并且具有许多毒力因素，使它们能够导致疾病。它们是全世界医院感染的可传播和重要原因。当将一种菌株传播给其他患者或通过社区中感染者的密切接触时，可能会发生MRSA爆发。我们的初步结果表明，OA是具有双触发性的生物分子：杀死MRSA细菌并增强宿主先天免疫。在这里，我们提出了三个特定的目的，以（a）研究内源性FFA在细菌杀死和宿主对FFA暴露的反应中的作用； （b）针对金黄色葡萄球菌/MRSA皮肤感染开发了FFA衍生的新治疗方法。三个具体的目的是（1）检查FFA的金黄色葡萄球菌菌株选择性，并使用FFAS缺陷型小鼠研究内源性FFA的抗恒星菌活性； （2）工程师通过物理化学分析探索纳米脂肪链球菌的基于纳米脂质体的FFA（纳米脂蛋白），并专门针对金黄色葡萄球菌并探索纳米脂肪的杀菌机理； （3）评估针对金黄色葡萄球菌感染的靶向纳米脂肪的效力，并评估宿主对靶向纳米脂肪的反应。 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生物学家（顾问Alan F. Hofmann博士）。成功后，该提案的结果将产生广泛的影响，因为（a）揭示内源性脂肪酸在先天免疫中的作用将为宿主 - 病原体相互作用开辟新的研究领域； （b）这项工作可以提供一种全新的方法来治疗MRSA和S.金黄色葡萄球菌相关的感染，从而使整个MRSA感染患者的整个社区受益于美国每年超过126,000名患者； （c）可能会使用类似的策略来治疗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。 公共卫生相关性： 金黄色葡萄球菌感染在皮肤和软组织上，占MRSA疾病的75％以上。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，因为内源性化合物会导致较低的耐药金黄色葡萄球菌菌株的风险较低，并且可能对患者产生较小的副作用。