选择性雌激素受体调节剂抑制变异链球菌的作用探究

Study on the inhibitory effect of selective estrogen receptor modulators on Streptococcus mutans

目的筛选小分子抗菌药物,探讨选择性雌激素受体调节剂(SERMs)对变异链球菌的抗菌作用及作用机制。方法采用微量稀释法,筛选426个美国食品药物管理局批准的小分子药物对变异链球菌的最低抑菌浓度,通过建立变异链球菌的随机突变体库,探究SERMs作用于变异链球菌的靶点。结果小分子药物库中归属于SERMs的托瑞米芬、他莫昔芬、克罗米芬和雷洛昔芬对变异链球菌具有良好的抗菌作用。通过构建变异链球菌的突变体库,筛选发现了两个突变菌株对克罗米芬产生了抗性,对耐药株的基因序列的分析表明,转座子插入位点位于smu_546、smu_874的基因。结论托瑞米芬、他莫昔芬、克罗米芬、和雷洛昔芬等SERMs药物对变异链球菌有明显的抗菌作用,且克罗米芬的作用靶点可能位于smu_546、smu_874基因表达的蛋白上。

Objective To screen small-molecule antibacterial drugs and investigate the antibacterial effect and mechanism of selective estrogen receptor modulators(SERMs)against Streptococcus mutans(S.mutans).Methods The minimum inhibitory concentration of 426 Food and Drug Administration(FDA)-approved small-molecule drugs against S.mutans was determined using the microdilution method,and the target of SERMs acting on S.mutans was explored by employing a random transposon mutant library.Results Among the 426 FDA-approved SERMs,toremiphene,tamoxifen,clomiphene,and raloxifene exhibited excellent antibacterial effects against S.mutans.Results of mutant library screening showed that the two mutant strains were resistant to clomiphene.The gene sequence of the resistant strains showed that the transposon insertion sites were located in the genes of smu_546 and smu_874.Conclusion SERMs,such as toremifene,tamoxifen,clomiphene,and raloxifene,exerted obvious antibacterial effects on S.mutans,and their targets may be proteins expressed by smu_546 and smu_874 gene.