Mechanisms of Metal Ion Homeostasis of Oral Streptococci

口腔链球菌金属离子稳态机制

• 批准号: 10680956
• 负责人: Jose A Lemos
• 金额: $ 45.53万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680956
• 关键词: ATP phosphohydrolase; Address; Affect; Animal Model; Anti-Inflammatory Agents; Area; Bacteria; Bioinformatics; Biological; Calculi; Cells; Computer Assisted; Data; Dental Hygiene; Dental Plaque; Dental caries; Development; Disease; Docking; Drug Design; Formulation; Functional disorder; Gingivitis; Goals; Halitosis; Health; Healthcare; Homeostasis; Human; Investigation; Ions; Life; Light; Mediating; Metals; Microbial Biofilms; Microbiology; Mind; Modality; Modeling; Molecular; Mouth Diseases; Mouthwash; Mutation Analysis; Names; Oral; Oral health; Pathway interactions; Pharmaceutical Chemistry; Physiological; Prevention; Property; Proteins; Rattus; Research; Research Personnel; Role; Saliva; Salivary; Salts; Shapes; Source; Streptococcus; Streptococcus mutans; Stress; Structure; Synthesis Chemistry; System; Therapeutic; Therapeutic Agents; Toothpaste; Toxic effect; Trace metal; Zinc; anticaries; antimicrobial; biological adaptation to stress; dental biofilm; human pathogen; inhibitor; innovation; microbial; microorganism interaction; multidisciplinary; new therapeutic target; novel; oral bacteria; oral biofilm; oral care; oral microbial community; oral microbiome; oral streptococci; pathogen; prevent; public database; rational design; therapeutic target; transcription factor; transcriptome

ABSTRACT Zinc (Zn) is an essential trace metal to all forms of life that becomes toxic at high concentrations. Because it has both antimicrobial and anti-inflammatory properties, Zn is used as a therapeutic agent to treat a variety of infectious and non-infectious human conditions. While the efficacy of Zn as an anticaries agent is somewhat controversial, Zn salts are used in several oral healthcare products to prevent calculus formation, treat gingivitis and halitosis, and to control dental plaque accumulation. However, the consequences of rising salivary Zn levels above physiological concentrations to microbial and host-pathogen interactions are poorly understood and warrant further investigation. Recently, we discovered that S. mutans, a keystone pathogen in dental caries, is inherently more tolerant to the toxic effects of Zn than other streptococci, including commensal species associated with oral health. Using transcriptome and mutational analysis approaches, we identified a previously uncharacterized P1B-type ATPase exporter and cognate transcriptional factor, which we respectively named ZccE and ZccR, as primarily responsible for the remarkable high Zn tolerance of S. mutans. Searching public databases, we found that ZccE is unique to S. mutans providing an opportunity for the development of Zn-based antimicrobial therapies specifically tailored to eliminate S. mutans. Our working hypotheses are that the ability to overcome Zn toxicity is an important aspect of S. mutans pathophysiology, and that the identification of ZccE inhibitors can pave the way for the development of a species-specific Zn-based therapeutic modality. With the long-term goal of developing new anticaries therapies in mind, the specific goals of this conceptually, technically, and translationally innovative application are: (i) to uncover the regulatory mechanisms and pathways that mediate Zn tolerance in S. mutans; (ii) to determine the implications of increasing Zn concentrations, above physiological levels, to the composition and homeostasis of the oral microbiome; and (iii) to explore and then develop ZccE as an antimicrobial target. To accomplish these goals, the PI assembled a multidisciplinary team of investigators with complementary expertise in molecular microbiology and animal models (Abranches and Lemos), structured-based computer-aided drug design (Li), and medicinal chemistry (Huigens and Li). Completion of this study will: (i) significantly advance our understanding of the regulatory mechanisms and pathways that mediate bacterial Zn tolerance with the potential of revealing new therapeutic targets; (ii) shed light onto the implications and potential of Zn-based therapies in oral health and, more specifically, in caries control; and (iii) facilitate the rational design of new antimicrobial therapies to prevent/control the emergence of cariogenic biofilms.

摘要 锌是所有生命形式必不可少的痕量金属，在高浓度下会变得有毒。因为它 同时具有抗菌和消炎的特性，锌被用作治疗多种疾病的治疗剂 有传染性和非传染性的人类状况。而锌作为一种防龋剂的效果有点 有争议的是，锌盐被用于几种口腔保健产品中，以防止结石形成，治疗 预防牙周炎和口臭，控制牙菌斑堆积。然而，上涨的后果是 唾液锌水平高于生理浓度对微生物和宿主-病原体的相互作用很差 我明白，并需要进一步调查。最近，我们发现了变形链球菌，一种重要的病原菌 龋齿，与生俱来对锌的毒性作用比其他链球菌更耐受，包括共生菌 与口腔健康有关的物种。使用转录组和突变分析方法，我们发现了一种 以前未知的P1B型ATPase输出子和同源转录因子，我们分别 命名为ZccE和ZccR，主要原因是变形链球菌对锌的耐受性极高。搜索 在公共数据库中，我们发现ZccE是变形链球菌所特有的，为变形链球菌的发展提供了机会 锌为基础的抗菌疗法，专门为消除变形链球菌而量身定做。我们的工作假设是 克服锌中毒的能力是变形链球菌病理生理学的一个重要方面，而锌毒性的克服能力 ZccE抑制剂的鉴定为开发物种特异性锌基化合物铺平了道路 治疗方式。考虑到开发新的防腐疗法的长期目标，具体目标 这一概念上、技术上和翻译上的创新应用是：(I)揭示监管 调节变形链球菌耐锌性的机制和途径；(Ii)确定 提高锌浓度，超过生理水平，对口腔的成分和动态平衡 探索并开发ZccE作为抗微生物靶标。为了实现这些目标， PI组建了一支由多学科调查人员组成的团队，在分子方面具有互补的专业知识 微生物学和动物模型(分支和LEMOS)，基于结构化的计算机辅助药物设计(LI)， 和药物化学(惠根斯和李)。这项研究的完成将：(I)大大推进我们的 了解细菌锌耐受性的调节机制和途径 揭示新的治疗靶点的潜力；(Ii)阐明锌的含义和潜力 口腔健康方面的治疗，更具体地说，在龋齿控制方面；以及(Iii)促进合理设计新的 预防/控制致龋性生物被膜出现的抗微生物疗法。