A novel strategy in antimicrobial drug discovery against Porphyromonas gingivalis

针对牙龈卟啉单胞菌的抗菌药物发现的新策略

• 批准号: 9136646
• 负责人: Victoria Nanette Stone
• 金额: $ 0.82万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2015-11-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136646
• 关键词: Active Sites; Adult; Affect; Antibiotics; Bacteria; Benign; Binding; Biochemical; Biological Assay; Cells; Clinical; Complex; Computer Simulation; Computers; Coupled; Dental Hygiene; Dental Plaque; Deterioration; Development; Disease; Disease Progression; Drug Design; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Essential Genes; Gene Targeting; Genes; Goals; Growth; Heart Diseases; Heart Valves; Immunologic Factors; Infection; Infective endocarditis; Knowledge; Lead; Ligaments; Link; Lung; Measures; Modeling; Molecular; Molecular Models; Oral; Oral cavity; Oral health; Oxidoreductase; Pathway interactions; Periodontal Diseases; Periodontitis; Persons; Pharmaceutical Preparations; Play; Population; Porphyromonas gingivalis; Property; Protein Binding; Proteins; Role; Streptococcus; Stroke; Structure; Surface; Systemic disease; Tissues; Tooth Loss; Tooth structure; Treatment Step; United States; Virulence Factors; antimicrobial; antimicrobial drug; base; drug discovery; inhibitor/antagonist; insight; microbial; microorganism; molecular modeling; novel strategies; novel therapeutic intervention; pathogen; periopathogen; prospective; public health relevance; respiratory; screening; three dimensional structure; three-dimensional modeling; tooth surface; virtual

DESCRIPTION (provided by applicant): Periodontal disease affects approximately 50% of the adult population in the United States and initiates with the establishment of a poly-microbial complex on the tooth surface more commonly known as dental plaque. Coupled with various immunological factors bacterial pathogens can trigger the deterioration of tooth supporting tissues, resulting in tooth loss. In addition to this, poor oral hygiene has been associated with systemic diseases such as infective endocarditis, a potentially lethal infection of the cardiac valves. While the oral cavity contains over 700 species of microorganisms, few species are known to contribute to the onset of periodontal disease. Clinical evidence suggests that Porphyromonas gingivalis plays a significant role in the progression of the disease, expressing numerous virulence factors that aid in the infection. Concerning periodontal disease, we hypothesize narrow spectrum antibiotics may be beneficial. By specifically targeting one of the primary pathogens, one could reduce the destructive factors triggering periodontitis while maintaining a person's healthy flora. Based on previous studies in the benign early colonizer Streptococcus sanguinis, we have knowledge of essential pathways and genes required for microbial growth and survival. With this knowledge in the foreground we believe we have the ability to predict essential gene targets in other microbial species. In our preliminary studies we analyzed these essential pathways to predict essential genes in P. gingivalis. We then compared the predicted essential genes to known essential genes in S. sanguinis and selected the enzyme diaminopimelate dehydrogenase as P. gingivalis "specific", which we confirmed to be essential. A 3D model of the protein has been created based off the crystal structure and is now being studied for its protein and binding properties. To further explore a species-specific drug discovery strategy we propose the following aims: (1) to identify a set of potential enzyme inhibitors utilizing in silico molecular modeling, (2) to determine the efficacy of our candidate antimicrobial compounds through target-based assays and (3) to select for antimicrobial properties through whole-cell based screening. Ultimately, these aims propose to identify a prospective antimicrobial agent specific to the periopathogen P. gingivalis, potentially demonstrating drugability and selectivity within a poly-microbial environment. Once completed, our study may give insight into a novel therapeutic approach when dealing with periodontal disease.

描述（由申请人提供）：牙周病影响着美国大约 50% 的成年人口，并始于牙齿表面上多种微生物复合物的形成，通常称为牙菌斑。再加上各种免疫因素，细菌病原体会引发牙齿支持组织的恶化，导致牙齿脱落。除此之外，口腔卫生不良还与感染性心内膜炎（一种可能致命的心脏瓣膜感染）等全身性疾病有关。虽然口腔含有 700 多种微生物，但已知很少有微生物会导致牙周病的发生。临床证据表明，牙龈卟啉单胞菌在疾病的进展中发挥着重要作用，表达大量有助于感染的毒力因子。关于牙周病，我们假设窄谱抗生素可能有益。通过专门针对一种主要病原体，可以减少引发牙周炎的破坏性因素，同时保持人体的健康菌群。根据之前对良性早期定植血链球菌的研究，我们了解了微生物生长和生存所需的基本途径和基因。有了这些知识，我们相信我们有能力预测其他微生物物种的重要基因目标。在我们的初步研究中，我们 分析了这些重要途径以预测牙龈卟啉单胞菌的必需基因。然后，我们将预测的必需基因与血链球菌中已知的必需基因进行比较，并选择二氨基庚二酸脱氢酶作为牙龈卟啉单胞菌“特异性”，我们确认其是必需的。该蛋白质的 3D 模型已根据晶体结构创建，目前正在研究其蛋白质和结合特性。为了进一步探索物种特异性药物发现策略，我们提出以下目标：（1）利用计算机分子模型确定一组潜在的酶抑制剂，（2）通过基于目标的测定确定我们的候选抗菌化合物的功效(3) 通过基于全细胞的筛选来选择抗菌特性。最终，这些目标旨在确定一种针对牙周病原菌牙龈卟啉单胞菌的前瞻性抗菌剂，有可能证明在多微生物环境中的成药性和选择性。一旦完成，我们的研究可能会为治疗牙周病提供一种新的治疗方法。