Indigenous Free Fatty Oleic acid Against MRSA Skin Infection

描述(由申请人提供)： 这项建议的中心目的是探索内源性油酸(OA)的抗金黄色葡萄球菌(S.aureus)活性。油酸是一种天然存在于人体的单不饱和omega-9游离脂肪酸(FFA)。金黄色葡萄球菌，特别是耐甲氧西林金黄色葡萄球菌(MRSA)是致病的，并具有许多毒力因子，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暴发。我们的初步结果表明，OA是一种具有双功能的生物分子：杀灭MRSA细菌和增强宿主天然免疫。在这里，我们提出了三个具体的目标：(A)研究内源性FFA在细菌杀灭和宿主对FFA暴露的反应中的作用；以及(B)开发一种基于FFA的治疗金黄色葡萄球菌/MRSA皮肤感染的新方法。具体的三个目标是：(1)检测FFAs对金黄色葡萄球菌的选择性，并利用FFAs缺陷小鼠观察内源性FFA的抗葡萄球菌活性；(2)设计一种针对金黄色葡萄球菌的纳米脂质体FFA(Nano-LipoFFA)，通过理化分析探索其杀菌机制；以及(3)评价靶向纳米LipoFFA对金黄色葡萄球菌皮肤感染的效力，以及评估宿主对靶向纳米LipoFFA的反应。为了进行建议的研究，我们成立了一支坚实的研究团队，成员包括两名细菌学家(黄俊明博士；Richard Gallo博士，联合研究员)、一名金黄色葡萄球菌专家(Victor Nizet博士，顾问)、两名纳米技术工程师(Mirianas Chachisvilis博士，联合研究员和张良芳博士，顾问)和一名脂类生物学家(Alan F.Hofmann博士，顾问)。如果成功，这项建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性免疫中的作用将开启宿主与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方法来治疗MRSA和金黄色葡萄球菌相关感染，从而使美国每年超过12.6万名MRSA感染患者受益；(C)类似的策略可能被用于治疗由其他细菌引起的各种感染或疾病，从而使更多的患者受益。 公共卫生相关性： 皮肤软组织金黄色葡萄球菌感染占耐甲氧西林金黄色葡萄球菌病的75%以上。使用内源性油酸治疗金黄色葡萄球菌/耐甲氧西林金黄色葡萄球菌皮肤感染将符合进化医学，因为内源性化合物导致开发新的抗药性金黄色葡萄球菌菌株的风险较低，并且可能对患者产生较少的副作用。

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.