叶酸途径的双靶点抑制剂可抑制内在性耐甲氧苄啶的二氢叶酸还原酶DfrB。
Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases.
作者信息
Toulouse Jacynthe L, Shi Genbin, Lemay-St-Denis Claudèle, Ebert Maximilian C C J C, Deon Daniel, Gagnon Marc, Ruediger Edward, Saint-Jacques Kévin, Forge Delphine, Vanden Eynde Jean Jacques, Marinier Anne, Ji Xinhua, Pelletier Joelle N
机构信息
Département de biochimie, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.
PROTEO, Quebec G1V 0A6, Canada.
出版信息
ACS Med Chem Lett. 2020 Sep 28;11(11):2261-2267. doi: 10.1021/acsmedchemlett.0c00393. eCollection 2020 Nov 12.
Abstract
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.
摘要
甲氧苄啶（TMP）被广泛用于治疗人类和家畜的感染，这加速了TMP耐药性的出现。新出现且大多未被追踪的II型二氢叶酸还原酶（DfrBs）是本质上具有TMP抗性的质粒携带型Dfrs，其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保守的，并且所有成员都对TMP抑制作用较弱，这与TMP抗性一致。我们研究了它们被已知的和新型的6-羟甲基-7,8-二氢蝶呤焦磷酸激酶（HPPK）双底物抑制剂抑制的情况。重要的是，所有成员都被HPPK抑制剂抑制，这使得这些分子成为两种严格意义上的微生物叶酸途径酶的双靶点抑制剂。
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