Oxidative Stress in Oral Streptococci

描述（由申请人提供）：拟议研究的长期目标是更全面地了解口腔链球菌的氧化应激和氧化损伤，并利用这些信息开发有效的抗菌药物来控制牙菌斑致病性，主要与龋齿有关。该项目的具体目标如下。特异性目标1侧重于更详细地定义变形链球菌对氧化应激的适应性反应。该定义将包括确定诱发反应的因素，包括酸化，但特别是有氧生长和暴露于巯基剂。确定这些反应的细节，特别是它们的生理调节，将取决于我们已经开发的遗传工具，包括保护酶和调节蛋白基因的突变。专项目标2涉及口腔链球菌呼吸作用的基础研究，特别是变形链球菌，包括直接从牙菌斑中分离的菌株，以及单生物和混合生物膜的使用。Aim的另一部分是更详细地定义氧化损伤的主要细胞靶点，特别是蛋白质，并评估抗氧化应激保护机制的能量学，其中大多数需要ATP， NADH和/或NADPH发挥作用。具体目标3侧重于小分子的转化研究，如锌阳离子、苯并咪唑或其他巯基反应剂，如大蒜素、螯合剂、氟化物和其他卤素、过渡金属阳离子和氧化抗菌剂。该研究将与前两个特定目标的基础研究紧密结合，以期利用基础信息开发增强口腔细菌氧化损伤的药物或药物组合。转化工作将包括单生物和混合生物膜的研究，以及测试抗菌剂的细胞/生物膜渗透性和保留性的测定，以帮助我们评估其在口腔预防和治疗方面的潜力。这项研究与公共卫生直接相关，主要是控制龋齿，龋齿是美国年轻人中最普遍的传染病，也是美国老年人日益严重的问题。这项工作包括基础研究和应用研究，旨在更好地了解牙菌斑细菌的生物学，特别是与氧代谢和活性氧引起的损伤有关的生物学。

DESCRIPTION (provided by applicant): The long-term objectives of the proposed research are to gain a more complete view of oxidative stress and oxidative damage to oral streptococci and to use this information to develop effective antimicrobial for control of Dental plaque pathogenicity, primarily related to Dental caries. The Specific Aims of the project are the following. Specific Aim 1 is focused on defining in more detail adaptive responses of S. mutans to oxidative stress. The definition will include determinations of factors that induce the responses, including acidification, but particularly aerobic growth and exposure to sulfhydryl agents. Determination of the details of these responses, especially their physiologic regulation, will depend on genetic tools we already have developed, including mutants in genes for protective enzymes and for regulatory proteins. Specific Aim 2 involves basic studies of respiration of oral streptococci, especially mutans streptococci, including strains isolated directly from Dental plaque, and use of mono-organism and mixed-organism biofilms. Another part of the Aim is to define in more detail the major cell targets for oxidative damage, especially proteins, and to assess the energetics of protective mechanisms against oxidative stress, most of which require ATP, NADH and/or NADPH to function. Specific Aim 3 is focused on translational research with investigation of small molecules, such as zinc cations, benzimidazoles or other sulfhydryl-reacting agents, such as allicin, chelators, fluoride and other halogens, transition metal cations and oxidative antimicrobials. The research will be closely interdigitated with the basic studies of the first 2 Specific Aims with a view to using of basic information in developing agents or combinations of agents potent for enhancing oxidative damage to oral bacteria. The translational work will include studies with mono-organism and mixed biofilms and determinations of cell/biofilm permeabilities to, and retentiveness of, the test antimicrobials to help us evaluate their potentials for prophylactic and therapeutic use in the mouth. The research is directly related to public health, primarily the control of Dental caries, which is the most prevalent infectious disease among young people in the American population and a growing problem for older Americans. The work involves basic and applied studies Aimed at a better understanding of the biology of Dental plaque bacteria related especially to oxygen metabolism and damage caused by reactive oxygen species.