Inhibition of oral bacterial biofilm formation using natural products-inspired or

使用天然产品启发或抑制口腔细菌生物膜形成

基本信息

批准号：
8048887
负责人：
Nathaniel Charles Cady
金额：
$ 10.59万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048887
关键词：
Actinomyces naeslundii Actinomycosis Address Affect Bacteria Behavior Biological Assay Biological Factors Biomimetics Biosensor Cells Collaborations Data Dental Hygiene Dental caries Development Disease Effectiveness Endocarditis Engineering Excision Foundations Future Goals Growth Health In Situ Infection Knowledge Laboratories Lead Libraries Liquid substance MUC5B gene Metabolic Pathway Methods Microbial Biofilms Microbiology Modeling Molecular Molecular Biology Molecular Weight Mouth Diseases Mouthwash Nanotechnology Oral Oral cavity Oral health Organism Outcome Pathway interactions Porphyromonas gingivalis Proteomics Pseudomonas aeruginosa Research Running Saliva Screening procedure Signal Pathway Signal Transduction Streptococcus Streptococcus mutans Structure System Technology Testing Therapeutic Therapeutic Uses Toothbrushing Training Universities VAI-2 Vibrio Work analog assay development bacterial resistance base college combat design experience feeding human disease improved inhibitor/antagonist innovation novel oral biofilm prevent professor prophylactic quorum sensing skills small molecule toothbrush

项目摘要

DESCRIPTION (provided by applicant): Oral bacterial biofilms are major contributors to tooth decay (dental caries) and are a potential conduit for infection and disease. These biofilms have been shown to contain hundreds of species of bacteria and are resistant to removal and eradication by traditional oral hygiene practices, such as frequent tooth brushing or oral rinsing with mouthwash. Novel prophylactic and in situ treatment methods are therefore needed to address this problem. The central hypothesis of this effort is that small molecule effectors can reduce or eradicate oral biofilm-formation through inhibition of bacterial signaling and related metabolic pathways. Preliminary studies in my laboratory have shown that natural product-inspired organic compounds have efficacy in reducing biofilm formation by model biofilm forming bacteria. These compounds do not affect bacterial growth and propagation, but directly inhibit biofilm formation, as demonstrated by planktonic growth assays and microplate-based biofilm assays. We hypothesize that these compounds directly affect cell signaling pathways that are involved in biofilm formation. For instance, quorum sensing autoinducers, such as autoinducer-2 (AI-2) have been shown to affect cellular behavior and biofilm formation for a broad range of distantly related bacteria. Using a biomimetic approach, a library of structurally-related, organic compounds will be synthesized and screened for reduction or inhibition of biofilm formation by oral biofilm-forming bacteria. We will focus on AI-2 as the core structure for construction of our library, since derivatives of this structure could have antagonistic activity on quorum sensing pathways which have been implicated in biofilm formation. This initial study will focus on three ecologically relevant organisms: Streptococcus mutans, Streptococcus sanguinis and Actinomyces naeslundii. S. mutans has been implicated in oral disease and caries formation, while S. sanguinis and A. naeslundii are oral pioneer-colonizing commensal organisms that are involved in initial establishment of oral biofilms. Furthermore, S. sanguinis and A. naeslundii are associated with significant human diseases including endocarditis and actinomycosis. Therefore, inhibition of biofilm formation by these organisms could prevent later colonization by pathogenic organisms, such as S. mutans or Porphyromonas gingivalis that lead to tooth decay and oral disease. Inhibition of biofilm formation by all of these organisms would therefore directly affect both oral and systemic health. Our approach is highly innovative because it focuses on direct antagonism of quorum sensing and biofilm formation pathways with structural derivatives of autoinducer compounds. Rather than screening large libraries of unrelated compounds, we believe that a focused design and synthesis approach will be more effective and will enable rational improvement of compound efficacy. This collaborative research effort will be led by Prof. Nathaniel Cady, and leverages collaborations with a bioorganic/synthetic chemist (Prof. Rabi Musah - University at Albany) and an expert in biofilms/bacterial signaling, Prof. Alexander Rickard (Binghamton University). We expect several significant outcomes from this work. We will identify small molecular inhibitors of oral bacterial biofilm formation and will evaluate their effectiveness in environmentally relevant model flow-based systems. We will also investigate the effects of these compounds on intercellular signaling, which will serve as a foundation for a future R21 or R01 proposal to elucidate their mechanism of action and systematic improvement of their activity through rational design/synthesis. PUBLIC HEALTH RELEVANCE: The central hypothesis of this effort is that small molecule effectors can inhibit oral biofilm-formation through antagonism of bacterial signaling and metabolic pathways. Using a biomimetic, natural products-inspired approach, a library of structurally-related, organic compounds will be synthesized and screened for effectiveness in reducing or inhibiting biofilm formation by common orally-associated bacteria. Compounds having a strong inhibitory effect on biofilm formation will then be tested in supplemented saliva-fed flow cells to mimic environmental conditions in the oral cavity. Finally, we will explore our hypothesis that these compounds function through modulation of cell signaling behavior. The results of these studies will serve as the basis for a R21 or R01 application to elucidate their mechanism of action and develop them for therapeutic or prophylactic use.

描述（由申请人提供）：口腔细菌生物膜是牙齿腐烂（龋齿）的主要贡献者，是感染和疾病的潜在管道。这些生物膜已被证明包含数百种细菌，并且可以通过传统的口腔卫生习惯（例如频繁刷牙或用漱口水进行口腔冲洗）抵抗去除和消除。因此，需要新颖的预防性和原位治疗方法来解决此问题。这项工作的中心假设是，小分子效应子可以通过抑制细菌信号传导和相关代谢途径来减少或根除口服生物膜形成。我的实验室的初步研究表明，自然产物启发的有机化合物在通过模型的生物膜形成细菌中降低生物膜形成方面具有疗效。这些化合物不会影响细菌的生长和繁殖，而是直接抑制生物膜的形成，如浮游生长测定和基于微板岩的生物膜测定所证明的那样。我们假设这些化合物直接影响与生物膜形成有关的细胞信号通路。例如，已经证明，诸如自动诱导仪-2（AI-2）之类的法定感应自动诱导剂会影响细胞行为和生物膜形成，以造成广泛相关的细菌。使用仿生方法，将合成与结构相关的有机化合物的库，并筛选以减少或抑制口服生物膜形成细菌的生物膜形成。我们将专注于AI-2作为构建图书馆的核心结构，因为该结构的衍生物可能对涉及生物膜形成的群体感应途径具有拮抗活性。这项最初的研究将集中于三种与生态相关的生物：链球菌，sanguinis链球菌和静脉肌动菌Naeslundii。 S. mutans与口腔疾病和龋齿形成有关，而S. sanguinis和A. naeslundii是口腔先驱 - 殖民化的共生生物，这些生物与初始建立口服生物膜有关。此外，S. sanguinis和naeslundii链球菌与包括心内膜炎和放线症的重大人类疾病有关。因此，这些生物对生物膜形成的抑制可以防止致病生物的后来定植，例如诱变链球菌或卟啉念珠菌，导致牙齿衰减和口腔疾病。因此，所有这些生物都会抑制生物膜形成，将直接影响口服和系统性健康。我们的方法具有很高的创新性，因为它专注于具有自动诱导剂化合物的结构衍生物的法定感应和生物膜形成途径的直接拮抗作用。我们认为，与其筛选大型化合物的大量库，我们认为专注的设计和合成方法将更加有效，并能够合理地提高复合功效。这项合作研究工作将由纳撒尼尔·卡迪（Nathaniel Cady）教授领导，并利用与生物有机/合成化学家（Rabi Musah教授 - 奥尔巴尼大学）和生物膜/细菌信号的专家，Alexander Rickard（宾汉顿大学）的专家。我们预计这项工作会带来一些重要的结果。我们将确定口服细菌生物膜形成的小分子抑制剂，并评估其在基于环境相关的基于模型的基于模型的系统中的有效性。我们还将研究这些化合物对细胞间信号的影响，这将是未来R21或R01提案的基础，以阐明它们的作用机理以及通过有理设计/合成的活动机理和系统的改善。公共卫生相关性：这项工作的核心假设是，小分子效应子可以通过细菌信号传导和代谢途径的拮抗作用来抑制口服生物膜形成。使用仿生，天然产物启发的方法，将合成和筛选与结构相关的有机化合物的库，以减少或抑制通过普通口服相关细菌的生物膜形成的有效性。然后，对生物膜形成具有很强抑制作用的化合物将在补充的唾液流动细胞中进行测试，以模仿口腔中的环境条件。最后，我们将探讨我们的假设，即这些化合物通过调节细胞信号行为的功能。这些研究的结果将作为R21或R01应用的基础，以阐明其作用机理并开发用于治疗或预防性使用的基础。