TAXIS Pharmaceuticals, Inc., R&D Department, 9 Deer Park Drive, Suite J-15, Monmouth Junction, NJ, 08852, USA.
J Antibiot (Tokyo). 2022 Jul;75(7):385-395. doi: 10.1038/s41429-022-00531-9. Epub 2022 May 26.
FtsZ inhibitors represent a new drug class as no drugs using this mode of action (MOA) have been approved by regulators. 3-alkoxy substituted 2,6-difluorobenzamide scaffold is one of the most studied FtsZ inhibitors among which the most promising anti-MRSA candidate TXA709 is in clinical trial. In this paper, we present the screening and evaluation of a benzamide class that is functionalized at the alkoxy fragment targeting Gram-negative bacteria. The variations in 3-alkoxy substitutions, specifically the hydroxylated alkyl residues to the secondary and stereogenic pseudo-benzylic carbon of their methyleneoxy linker, are particularly active against K. pneumoniae ATCC 10031 in marked contrast to the derivatives related to PC190723, all of which were inactive against Gram-negative bacteria. The two lead molecules TXA6101 and TXY6129 inhibit the polymerization of E. coli FtsZ in a concentration-dependent manner and induce changes in the morphology of E. coli and K. pneumoniae consistent with inhibition of cell division. These classes of compounds, however, were found to be substrates for efflux pumps in Gram-negative bacteria.
FtsZ 抑制剂代表了一个新的药物类别，因为没有监管机构批准使用这种作用模式 (MOA) 的药物。3-烷氧基取代的 2,6-二氟苯甲酰胺支架是研究最多的 FtsZ 抑制剂之一，其中最有前途的抗耐甲氧西林金黄色葡萄球菌候选药物 TXA709 正在进行临床试验。在本文中，我们介绍了针对革兰氏阴性菌的烷氧基片段功能化的苯甲酰胺类的筛选和评估。3-烷氧基取代的变化，特别是羟基化的烷基残基与亚甲基氧连接物的假苄基碳原子的立体异构，对肺炎克雷伯菌 ATCC 10031 特别有效，与与 PC190723 相关的衍生物形成鲜明对比，所有这些衍生物对革兰氏阴性菌均无活性。两种先导化合物 TXA6101 和 TXY6129 以浓度依赖的方式抑制大肠杆菌 FtsZ 的聚合，并诱导大肠杆菌和肺炎克雷伯菌形态发生变化，与细胞分裂抑制一致。然而，这些化合物类别被发现是革兰氏阴性菌中外排泵的底物。
