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）：牙周疾病影响美国大约50％的成年人口，并通过在牙齿表面建立多微生物络合物的启动，通常称为牙菌斑。结合各种免疫学因素，细菌病原体会触发牙齿支撑组织的恶化，从而导致牙齿脱落。除此之外，口腔卫生不良与系统性疾病（例如感染性心内膜炎）有关，这可能是心脏瓣膜的致命感染。虽然口腔含有700多种微生物，但已知很少有物种会导致牙周疾病的发作。临床证据表明，牙龈卟啉单胞菌在疾病的进展中起着重要作用，表达了许多有助于感染的毒力因子。关于牙周疾病，我们假设狭窄的光谱抗生素可能是有益的。通过专门针对的一种主要病原体，可以减少触发牙周炎的破坏性因素，同时保持人的健康菌群。基于先前在良性早期结肠菌链球菌的研究中，我们了解了微生物生长和生存所需的必要途径和基因。有了在前景中的知识，我们认为我们有能力预测其他微生物物种中的基因靶标。在我们的初步研究中 分析了这些基本途径，以预测牙龈疟原虫中的必要基因。然后，我们将预测的必需基因与豆类葡萄球菌中的已知必需基因进行了比较，并选择了二氨基二二二二二酰二氢化酯酶为牙龈疟原虫“特定”，我们确认这是必不可少的。该蛋白质的3D模型是基于晶体结构而创建的，现在正在研究其蛋白质和结合特性。为了进一步探索一种特定物种的药物发现策略，我们提出了以下目的：（1）确定利用用于硅分子建模中的一组潜在酶抑制剂，（2）确定候选抗菌抗菌化合物的功效，通过基于目标的分析和（3）通过基于抗菌胞的基于群体的筛选。最终，这些目的建议识别针对牙龈牙周牙周牙或齿轮虫特异性的前瞻性抗菌剂，从而有可能在多微晶环境中证明可药物性和选择性。完成后，我们的研究可能会深入了解牙周疾病时的一种新型治疗方法。