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.

抽象的 锌（Zn）是对所有形式的生命形式的必需痕量金属，在高浓度下变得有毒。因为它 Zn具有抗菌和抗炎特性，用作治疗多种的治疗剂 传染性和非感染的人类状况。 Zn作为抗邦剂的功效有些 有争议的锌盐用于几种口腔保健产品中，以防止微积分形成，治疗 牙龈炎和盐症，并控制牙菌斑的积累。但是，上升的后果 唾液锌水平高于微生物和宿主 - 病原体相互作用的生理浓度很差 理解并保证进一步调查。最近，我们发现S. Mutans是一种Keystone病原体 与其他链球菌相比，龋齿对Zn的毒性作用更具宽容性，包括Consensal 与口腔健康相关的物种。使用转录组和突变分析方法，我们确定了 以前未表征的P1B型ATPase Exporter和Cognate转录因子分别我们分别 命名为ZCCE和ZCCR，主要负责S. mutans的显着高Zn耐受性。搜索 公共数据库，我们发现ZCCE是S. Mutans独有的，为开发的机会提供了机会 基于Zn的抗菌疗法是针对消除链球菌的专门量身定制的。我们的工作假设是 克服锌毒性的能力是链球菌病理生理学的重要方面，并且 识别ZCCE抑制剂可以为发展基于Zn的特定物种的发展铺平道路 治疗方式。长期目标是开发新的抗野赛疗法，具体目标 在概念，技术上和翻译上的创新应用中，它是：（i）揭示监管 介导S. mutans中Zn耐受性的机制和途径； （ii）确定 将Zn浓度提高到生理水平以上，口服的组成和稳态 微生物组； （iii）探索然后将ZCCE作为抗菌靶标。为了实现这些目标， PI组建了一个具有互补专业知识的研究人员的多学科团队 微生物学和动物模型（ABRANCHES和LEMOS），基于结构化的计算机辅助药物设计（LI）， 和药物化学（Huigens and Li）。这项研究的完成将：（i）大大提高我们的 了解介导细菌锌耐受性的调节机制和途径 揭示新的治疗靶标的潜力； （ii）将灯光放在基于Zn的含义和潜力上 口腔健康的疗法，更具体地说，是龋齿控制的； （iii）促进新的合理设计 抗菌疗法以防止/控制致癌生物膜的出现。