Skin Microbiome Editing with Fermentation Initiator

使用发酵引发剂编辑皮肤微生物组

基本信息

批准号：
9407254
负责人：
CHUN-MING HUANG
金额：
$ 22.5万
依托单位：
SURFACE BIOADVANCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407254
关键词：
Abscess Acne Acne Vulgaris Aerobic Anaerobic Bacteria Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotics Bacteria Bacteriophages Biological Biopsy Butyric Acids California Carbohydrates Carbon Charge Clinic Clinical Clinical Trials Unit Collaborations DNA Dermatologic Dermatology Development Disadvantaged Disease Effectiveness FDA approved Fees Fermentation Generations Glucose Glycerol Goals Growth Health Histone Deacetylase Histone Deacetylase Inhibitor Homeostasis Human Human Microbiome Immunosuppression In Vitro Individual Inflammation Inflammatory Lactose Lesion Microbe Nonesterified Fatty Acids Operative Surgical Procedures Pathogenicity Patients Pattern Polyethylene Glycols Probiotics Propionibacterium acnes Publications Reporting Research Resistance Role Services Site Skin Source Staphylococcus epidermidis Surface Symbiosis Techniques Technology Testing Transdermal substance administration Universities Virulence Factors Volatile Fatty Acids bactericide base biomaterial compatibility cytokine design experimental study fighting in vivo killings microbial microbiome microorganism pathogen receptor skin microbiome

项目摘要

Abstract Acne dysbiosis is defined as microbial imbalance with the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. We have demonstrated that Staphylococcus epidermidis (S. epidermidis), a probiotic bacterium co-existed with P. acnes in an acne lesion, can exploit the carbohydrate fermentation to produce short-chain fatty acids (SCFAs) and rein in the over-growth of P. acnes. In collaboration with Surface Bioadvances Inc. in San Diego, we have developed polyethylene glycol dimethacrylate (PEG-DMA), α-Lactose monohydrate (ALM), and propargyl-PEG5-tetra-Ac-beta-D-glucose as selective fermentation initiators (SFIs) which can specifically intensify fermentation activity of S. epidermidis, but not P. acnes. In this proposal, we will synthesize various PEG-carbohydrate conjugates as SFIs and identify the most potent SFI for rebalancing the dysbiotic acne vulgaris. The effects of SFIs on the suppression of P. acnes growth and reduction of {P. acnes-induced inflammation} will be investigated. We have recently obtained acne biopsies in partnership with Dr. Tissa R. Hata, a Director of the Dermatology Clinical Trials Unit at University of California, San Diego (UCSD). These acne biopsies have been used to establish ex vivo acne explants. The effectiveness of SFIs on suppression of P. acnes growth and reduction of pro-inflammatory cytokines will be tested by using ex vivo acne explants. Three Specific Aims are proposed to verify our hypothesis. In Specific Aim 1, we will compare the differential potencies of PEG macromers and their carbohydrate conjugates as SFIs for S. epidermidis, and investigate the broad-spectrum capability of SFI fermentation in growth inhibition of various clinical P. acnes strains. In Specific Aim 2, we will determine the efficacy of SFI fermentation for treatment of different inflammatory stages of acne vulgaris, {and examine the effect of SFI fermentation on the bacterial abundance in the acne microbiome.} In Specific Aim 3, we will {compare the anti-P. acnes potency of SFIs with SCFAs,} and explore the possible anti-comedogenic or toxic activities of SFIs. We envision that SFIs are able to specifically intensify the probiotic ability of S. epidermidis, produce SCFAs to “beat” out its competitor (P. acnes). {The use of SFI to initiate fermentation of probiotic S. epidermidis can avoid difficulty in determining how many SCFAs in a mixture can be formulated as anti-P. acnes agents.} When successful, the SFI will be {the first fermentation initiator that can edit/reshape dysbiotic microbiome without using live microorganisms such as live bacteria or bacteriophages.}

抽象的痤疮生态失调被定义为痤疮丙酸杆菌过度生长导致微生物失衡（痤疮丙酸杆菌）在痤疮微生物组中我们已经证明表皮葡萄球菌（S. epidermidis），一种与痤疮丙酸杆菌共存于痤疮病变处的益生菌，可以利用碳水化合物的发酵与痤疮丙酸杆菌合作生产短链脂肪酸 (SCFA) 并抑制痤疮丙酸杆菌的过度生长。位于圣地亚哥的 Surface Bioadvances Inc.，我们开发了聚乙二醇二甲基丙烯酸酯 (PEG-DMA)， α-乳糖一水合物 (ALM) 和炔丙基-PEG5-四-Ac-β-D-葡萄糖作为选择性发酵引发剂（SFI）可以特异性增强表皮葡萄球菌的发酵活性，但不能增强痤疮丙酸杆菌的发酵活性。根据该提案，我们将合成各种 PEG-碳水化合物缀合物作为 SFI，并确定最有效的 SFI 用于重新平衡失调性痤疮 SFI 对抑制痤疮丙酸杆菌生长的作用。和减少{P.痤疮引起的炎症}我们最近获得了痤疮。与大学皮肤科临床试验部主任 Tissa R. Hata 博士合作进行活检这些痤疮活检已用于建立离体痤疮外植体。 SFI 对抑制痤疮丙酸杆菌生长和减少促炎细胞因子的有效性将使用离体痤疮外植体进行测试。提出了三个具体目标来验证我们的假设。在具体目标 1 中，我们将比较 PEG大分子单体及其碳水化合物缀合物作为表皮葡萄球菌的SFI的不同效力，以及研究 SFI 发酵对各种临床痤疮丙酸杆菌生长抑制的广谱能力在具体目标 2 中，我们将确定 SFI 发酵对不同菌株的治疗效果。寻常痤疮的炎症阶段，{并检查 SFI 发酵对细菌丰度的影响在具体目标 3 中，我们将{比较 SFI 与 SCFA 的抗痤疮丙酸杆菌功效，} 并探索 SFI 可能的抗粉刺或毒性活性。我们预计 SFI 能够专门增强表皮葡萄球菌的益生能力，产生 SCFA“击败”其竞争对手（痤疮丙酸杆菌）{使用 SFI 启动益生菌 S. epidermidis 可以避免确定混合物中有多少 SCFA 可以配制为抗 P 的困难。痤疮制剂。}成功后，SFI 将成为{第一个可以编辑/重塑的发酵引发剂不使用活细菌或噬菌体等活微生物的失调微生物组。}