Trimethoprim (TMP) is widely used to treat infections in humans and in livestock, accelerating the incidence of TMP resistance. The emergent and largely untracked type II dihydrofolate reductases (DfrBs) are intrinsically TMP-resistant plasmid-borne Dfrs that are structurally and evolutionarily unrelated to chromosomal Dfrs. We report kinetic characterization of the known DfrB family members. Their kinetic constants are conserved and all are poorly inhibited by TMP, consistent with TMP resistance. We investigate their inhibition with known and novel bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). Importantly, all are inhibited by the HPPK inhibitors, making these molecules dual-target inhibitors of two folate pathway enzymes that are strictly microbial.

中文翻译：

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叶酸途径的双靶标抑制剂抑制固有甲氧苄啶抗性 DfrB 二氢叶酸还原酶

甲氧苄啶 (TMP) 被广泛用于治疗人类和牲畜的感染，加速了 TMP 耐药性的发生。新出现的且很大程度上未被追踪的 II 型二氢叶酸还原酶 (DfrBs) 本质上是 TMP 抗性质粒携带的 Dfrs，在结构和进化上与染色体 Dfrs 无关。我们报告了已知 DfrB 家族成员的动力学特征。它们的动力学常数是守恒的，并且都不受 TMP 的抑制，这与 TMP 抗性一致。我们研究了它们对 6-羟甲基-7,8-二氢蝶呤焦磷酸激酶 (HPPK) 的已知和新型双底物抑制剂的抑制作用。重要的是，所有这些都被 HPPK 抑制剂抑制，使这些分子成为两种严格微生物的叶酸途径酶的双重目标抑制剂。