New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans.
New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans.
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新型二氢叶酸还原酶小分子抑制剂抑制变形链球菌
DOI：
10.1016/j.ijantimicag.2015.03.015
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发表时间：
2015-08
影响因子：
10.8
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Zhang Q;Nguyen T;McMichael M;Velu SE;Zou J;Zhou X;Wu H
变形链球菌是龋齿的主要病原体。生物膜的形成是变形链球菌的关键毒力因子。抑制变形链球菌生物膜的药物可能具有治疗潜力。二氢叶酸还原酶（DHFR）在调节叶酸代谢中起着至关重要的作用。因此，DHFR 抑制剂是有效的药物，并已被探索作为抗癌剂和抗菌剂。在这项研究中，筛选了基于 DHFR 抑制剂曲美曲沙 (TMQ)（FDA 批准的药物）的类似物库，并鉴定了三种选择性抑制变形链球菌的新类似物。最有效的抑制剂对变形链球菌生物膜的 50% 抑制浓度 (IC50) 为 454.0 ± 10.2 nM，对 DHFR 的 50% 抑制浓度 (IC50) 为 8.7 ± 1.9 nM。相比之下，该化合物对人 DHFR 的 IC50 约为。 1000 nM，其效力下降>100倍，证明了类似物的高选择性。对变形链球菌生物膜表现出最低效力的类似物也具有最低的抑制变形链球菌DHFR的活性，进一步表明生物膜的抑制与降低的DHFR活性有关。这些数据以及有效类似物与建模的 DHFR 结构的对接表明，TMQ 类似物确实通过靶向 DHFR 选择性地抑制变形链球菌。因此，这些有效且选择性的小分子是有前途的先导化合物，可用于开发新的有效疗法来预防和治疗龋齿。
Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S. mutans were identified. The most potent inhibitor had a 50% inhibitory concentration (IC50) of 454.0 ± 10.2 nM for the biofilm and 8.7 ± 1.9 nM for DHFR of S. mutans. In contrast, the IC50 of this compound for human DHFR was ca. 1000 nM, a >100-fold decrease in its potency, demonstrating the high selectivity of the analogue. An analogue that exhibited the least potency for the S. mutans biofilm also had the lowest activity towards inhibiting S. mutans DHFR, further indicating that inhibition of biofilms is related to reduced DHFR activity. These data, along with docking of the potent analogue to the modelled DHFR structure, suggested that the TMQ analogues indeed selectively inhibited S. mutans through targeting DHFR. These potent and selective small molecules are thus promising lead compounds to develop new effective therapeutics to prevent and treat dental caries.