Beuchel Andreas, Robaa Dina, Negatu Dereje A, Madani Abdeldjalil, Alvarez Nadine, Zimmerman Matthew D, Richter Adrian, Mann Lea, Hoenke Sophie, Csuk René, Dick Thomas, Imming Peter
Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany, Kurt-Mothes-Str. 3, 06120 Halle (Saale), Germany.
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
ACS Med Chem Lett. 2022 Feb 28;13(3):417-427. doi: 10.1021/acsmedchemlett.1c00549. eCollection 2022 Mar 10.
causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 () is a piperidine-4-carboxamide (P4C) with bactericidal properties against . We recently identified DNA gyrase as the molecular target of . Here, we present docking and genetic evidence suggesting that P4Cs display a similar binding mode to DNA gyrase as gepotidacin. Gepotidacin is a member of the Novel Bacterial Topoisomerase Inhibitors (NBTIs), a new class of nonfluoroquinolone DNA gyrase poisons. Thus, our work suggests that P4Cs present a novel structural subclass of NBTI. We describe structure-activity relationship studies of leading to analogues showing increased antibacterial activity. Selected derivatives were tested for their inhibitory activity against recombinant DNA gyrase. Further optimization of the lead structures led to improved stability in mouse plasma and increased oral bioavailability.
会引发难以治愈的肺部感染。这种细菌对大多数抗感染药物耐药，包括一线抗结核药物。MMV688844（）是一种对具有杀菌特性的哌啶-4-甲酰胺（P4C）。我们最近确定DNA促旋酶是其分子靶点。在此，我们展示对接和遗传学证据，表明P4C与吉波沙星一样，对DNA促旋酶具有相似的结合模式。吉波沙星是新型细菌拓扑异构酶抑制剂（NBTI）的一员，这是一类新型的非氟喹诺酮类DNA促旋酶毒药。因此，我们的工作表明P4C是NBTI的一个新型结构亚类。我们描述了导致抗菌活性增强的类似物的构效关系研究。对选定的衍生物进行了针对重组DNA促旋酶的抑制活性测试。对先导结构的进一步优化提高了其在小鼠血浆中的稳定性并增加了口服生物利用度。
