Department of Chemistry, Worcester State University, 486 Chandler Street, Worcester, MA 01602, USA.
Acurx Pharmaceuticals LLC, 22 Camelot Court, White Plains, NY 10603, USA.
Bioorg Med Chem. 2019 Aug 1;27(15):3209-3217. doi: 10.1016/j.bmc.2019.06.017. Epub 2019 Jun 11.
Despite the growing global crisis caused by antimicrobial drug resistance among pathogenic bacteria, the number of new antibiotics, especially new chemical class of antibiotics under development is insufficient to tackle the problem. Our review focuses on an emerging class of antibacterial therapeutic agents that holds a completely novel mechanism of action, namely, inhibition of bacterial DNA polymerase IIIC. The recent entry of this new class into human trials may herald the introduction of novel drugs whose novel molecular target precludes cross-resistance with existing antibiotic classes. This review therefore examines the evolution of DNA pol IIIC inhibitors from the discovery of 6-(p-hydroxyphenylazo)uracil (HPUra) in the 1960s to the development of current first-in-class N7-substituted guanine drug candidate ACX-362E, now under clinical development for the treatment of Clostridioides difficile infection.
尽管由病原菌对抗菌药物的耐药性引发的全球危机日益严重，但新抗生素的数量，尤其是处于开发中的新型化学类别抗生素的数量，不足以解决这个问题。我们的综述重点关注一类新兴的抗菌治疗药物，其具有完全新颖的作用机制，即抑制细菌 DNA 聚合酶 IIIC。该新型药物最近已进入人体试验，这可能预示着新型药物的问世，其新颖的分子靶标可防止与现有抗生素类别产生交叉耐药性。因此，本综述从 20 世纪 60 年代发现 6-(对羟苯偶氮)尿嘧啶（HPUra）开始，考察了 DNA pol IIIC 抑制剂的发展历程，一直到目前处于临床开发阶段、用于治疗艰难梭菌感染的 N7-取代鸟嘌呤药物先导化合物 ACX-362E 的开发。
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