Nijampatnam Bhavitavya, Ahirwar Parmanand, Pukkanasut Piyasuda, Womack Holly, Casals Luke, Zhang Hua, Cai Xia, Michalek Suzanne M, Wu Hui, Velu Sadanandan E
Department of Chemistry, Department of Pathology, and Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
Department of Integrative Biomedical and Diagnostic Sciences, Oregon Health and Science University, Portland, Oregon 97239, United States.
ACS Med Chem Lett. 2020 Dec 7;12(1):48-55. doi: 10.1021/acsmedchemlett.0c00373. eCollection 2021 Jan 14.
Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium . readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, , and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as and . This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, , showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries.
龋齿是一种以牙釉质脱矿为特征的细菌性传染病。用传统抗生素治疗这种疾病基本上无效，因为致龋菌会形成坚韧的生物膜，对这种治疗具有抗性。龋齿的主要病原体是细菌 。 很容易在牙齿表面形成生物膜，并迅速从膳食蔗糖中产生乳酸。 分泌的葡糖基转移酶（Gtfs）主要负责产生对生物膜结构至关重要的胞外多糖。因此，抑制 Gtfs是开发不影响口腔共生菌生长的选择性生物膜抑制剂的有效方法。在此，我们报告了一个由90种先前鉴定的先导化合物 的类似物组成的文库，并对其构效关系（SAR）进行了探索。评估了所有化合物对 生物膜和细菌生长的抑制作用。使用酶谱分析法进一步评估了从该文库中选出的化合物对Gtfs的酶抑制作用，以及对口腔共生细菌物种如 和 的生长抑制作用。这项研究发现了几种具有更高效力和选择性的新型生物膜抑制剂。其中一个先导化合物 在龋齿大鼠模型中，颊面、龈沟和邻面龋损评分显著降低。
