耐季铵盐戈登链球菌对牙菌斑微生态影响及耐药机制研究

Quaternary ammonium salts (QAs) are a class of cationic surfactants with broad spectrum antibacterial activity. Dental materials modified with QAs exhibit good antibacterial and anti-caries performance, which has been successfully applied into dental clinic. However, as an antibacterial agent, a new problem has appeared in the use of QAs: Drug Resistance. Studies have reviewed that, in common oral flora, Streptococcus gordonii can develop drug resistance to QAs, possibly by means of changing its cell membrane permeability. However, the result remains in phenomena which lacks corresponding pathways and mechanisms studies. In addition, the effect of QAs-resistant Streptococcus gordonii on plaque micro-ecology remains to be studied. Therefore, we aimed at studying effects of QAs-resistant Streptococcus gordonii on bacterial interspecies competition and on cariogenicity of dental plaque, followed by studying its resistance pathways and mechanism, in order to provides a theoretical basis for drug-resistance prevention and clinical application of QAs.

季铵盐是一类具有广谱抗菌作用的阳离子表面活性剂，季铵盐改性后的牙科材料在抗菌防龋方面表现优异，已成功转化投入口腔临床使用中。然而作为一种抗菌剂，季铵盐的应用中也出现了一些新问题：细菌耐药性。目前研究发现，在口腔常见菌群中戈登链球菌可对季铵盐产生耐药作用，但前期研究尚停留在表型，缺乏相应的通路和机制研究。前期研究也缺乏关注耐药株的出现对口腔菌斑微生态造成的影响。因此，本课题针对目前季铵盐在龋病防治应用中遇到的问题：戈登链球菌耐药株的出现，首先从菌斑生态角度，通过研究耐药株和致龋菌菌间竞争关系和耐药株对菌斑生物膜致龋性的影响，评估耐药株的出现对菌斑微生态平衡的作用；其次从耐药机制角度，通过对耐药靶点的定位和耐药基因的筛选验证，探究出现耐药的通路和机制，为季铵盐的临床应用和耐药防控提供理论基础，也为口腔抗菌药物研发提供新思路。

作为一种广谱抗菌剂，季铵盐的口腔临床应用中出现了一些新问题：细菌耐药性。目前研究发现，在口腔常见菌戈登链球菌可对季铵盐产生耐药作用，但前期研究尚停留在表型，缺乏相应的通路和机制研究，也缺乏关注耐药株的出现对口腔菌斑微生态造成的影响。在耐药机制方面，本课题针对目前耐季铵盐戈登链球菌耐药株现状，通过表型研究及全基因组测序分析，筛选出耐药关键基因，并发现耐药关键基因可影响胞内活性氧自由基水平介导耐药，组学检测进一步发现了耐药关键基因可通过双组分信号系统ComDE介导季铵盐杀菌与耐药。在菌斑微生态方面，本课题研究了季铵盐短期应用环境下的菌斑生物膜微生态平衡，探索了可能改善耐药的季铵盐应用形式：pH响应性季铵盐智能材料，为季铵盐的临床应用和耐药防控提供了一定理论基础。