Bacterial fermentation in skin microbiome as probiotics (Bfismp) against S. aureu

描述(申请人提供)：细菌干扰造成共生细菌和致病物种之间的生态竞争。就像成熟水果中通过发酵进行的微生物竞争一样，通过发酵进行的细菌干扰在 深层皮肤脓肿是厌氧微环境，允许细菌将碳水化合物发酵成短链脂肪酸(SCFA)。酸奶是用肠道友好菌发酵牛奶，是平衡人体肠道细菌生态系统的极佳助剂。以往的研究表明，皮肤中的单链脂肪酸在影响细菌在正常人皮肤上的优势停留方面发挥了重要作用。因此，我们推测人类皮肤共生菌的发酵产物，如用友好的肠道细菌发酵制成的酸奶，可以作为皮肤益生菌来治疗病原体引起的皮肤感染。在这项建议中，我们将使用皮肤微生物组中的细菌发酵作为益生菌(BFISMP)来对抗耐甲氧西林金黄色葡萄球菌(MRSA)。由于耐甲氧西林金黄色葡萄球菌对多种传统抗生素的强大耐药性，开发有效的治疗方法仍然是一个尚未解决的挑战。每个人都携带痤疮丙酸杆菌(P.acnes)，这是一种革兰氏阳性和皮肤共生细菌，占皮肤微生物总数的50%以上。痤疮假单胞菌因其能将碳水化合物发酵成丙酸而得名。我们的初步结果表明，丙酸在体外和体内都有效地抑制了USA300的生长，USA300是一种社区获得的MRSA。更有趣的是，我们还证明了痤疮假单胞菌的发酵培养基对USA300的生长有抑制作用。我们提出的三个具体目标是：1)利用BFISMP治疗金黄色葡萄球菌/MRSA感染，建立BFISMP中SCFA的图谱，并检测抗S。方法：1)体外培养金黄色葡萄球菌/耐甲氧西林金黄色葡萄球菌；2)探讨其降低金黄色葡萄球菌/MRSA细胞内pH值的作用机制，验证其体内抑制金黄色葡萄球菌/耐甲氧西林金黄色葡萄球菌皮肤感染的作用；3)检测皮肤细胞对该药物的反应，检测局部应用该药物可能产生的副作用。STTR第一阶段项目将在加州大学圣地亚哥分校和Surface BioAdvance Inc.之间的合作基础上进行，Surface BioAdvance Inc.是圣地亚哥的一家公司，业务目标是开发针对传染病的疗法。我们已经形成了一支坚实的研究团队，由皮肤细菌学家(黄博士；加州大学圣迭戈分校的Pi博士)、分子生物学家(Surface BioAdvance Inc.的江博士)、皮肤科医生(Galo博士)和微生物学家(Nizet博士)组成。如果成功，从皮肤共生细菌发酵中提取的杀菌剂将使整个美国MRSA感染患者社区受益，该社区每年有超过12.6万名患者。这项提议的影响包括开辟一个新的护肤业，使用BFISMP治疗皮肤感染和/或促进皮肤健康。

DESCRIPTION (provided by applicant): Bacterial interference creates an ecological competition between commensal bacteria and pathogenic species. Like microbial competition via fermentation in a ripening fruit, bacterial interference via fermentation has been found in the deep-seated skin abscesses where is an anaerobic microenvironment, allowing bacteria to ferment carbohydrates to short-chain fatty acids (SCFA). Fermentation of milk with gut- friendly bacteria, yogurt is an excellent aid to balance the bacteriological ecosystem in the human intestine. Previous studies indicated that SCFAs in skin played a curial role in influencing the predominant residence of bacteria on normal human skin. Thus, we hypothesize that fermentation products of human skin commensal bacteria, like yogurt made by fermentation with friendly gut bacteria, can function as skin probiotics for treatment of skin infections by pathogens. In this proposal, we will use the bacterial fermentation in skin microbiome as probiotics (Bfismp) against methicillin-resistant Staphylococcus aureus (MRSA). It remains as an unmet challenge to develop effective therapeutics for MRSA treatment because of its formidable resistance against multiple traditional antibiotics. Everyone carried Propionibacterium acnes (P. acnes), a Gram-positive and skin commensal bacterium accounting for more than 50% of the total skin microbiome. P. acnes was named for its ability to ferment carbohydrates to propionic acid. Our preliminary results have demonstrated that propionic acid effectively suppressed the growth of USA300, a community-acquired MRSA, both in vitro and in vivo. More intriguingly, we also demonstrated that fermented media (acted as Bfismp) of P. acnes exerted an inhibitory effect on the growth of USA300. Three Specific Aims we proposed are to 1) Use the Bfismp against S. aureus/MRSA infection, establish the profiles of SCFA in Bfismp, and examine the anti-S. aureus/MRSA activity of Bfismp in vitro; 2) Explore the action mechanism of Bfismp on decreasing the intracellular pH of S. aureus/MRSA, and validate the in vivo potency of Bfismp in inhibiting skin infection of S. aureus/MRSA; and 3) Determine the response of skin cells to Bfismp, and test the possible side effects caused by topical application of Bfismp. The STTR Phase I project will be conducted based on collaboration between University of California, San Diego and Surface Bioadvances Inc., a San Diego company with a business aim to develop therapeutics against infectious diseases. We have formed a solid research team consisting of a skin bacteriologist (Dr. Huang; PI at UCSD), a molecular biologist (Dr. Jiang at Surface Bioadvances Inc.), a dermatologist (Dr. Gallo), and microbiologist (Dr. Nizet). When successful, bactericides derived from fermentation of skin commensal bacteria will benefit the entire community of patients with MRSA infections consisting of over 126,000 patients per year in United States. The impact of this proposal includes opening a novel skin-care industry of using Bfismp for treating skin infection and/or promoting skin health.