Department of Chemistry, Washington University in St. Louis, One Brookings Drive, St. Louis, Missouri 63130, United States.
The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, 4513 Clayton Avenue, St. Louis, Missouri 63108, United States.
J Med Chem. 2023 Mar 23;66(6):3917-3933. doi: 10.1021/acs.jmedchem.2c01629. Epub 2023 Mar 6.
Tetracyclines (TCs) are an important class of antibiotics threatened by an emerging new resistance mechanism─enzymatic inactivation. These TC-inactivating enzymes, also known as tetracycline destructases (TDases), inactivate all known TC antibiotics, including drugs of last resort. Combination therapies consisting of a TDase inhibitor and a TC antibiotic represent an attractive strategy for overcoming this type of antibiotic resistance. Here, we report the structure-based design, synthesis, and evaluation of bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). By appending a nicotinamide isostere to the C9 position of the aTC D-ring, we generated bisubstrate TDase inhibitors. The bisubstrate inhibitors have extended interactions with TDases by spanning both the TC and presumed NADPH binding pockets. This simultaneously blocks TC binding and the reduction of FAD by NADPH while "locking" TDases in an unproductive FAD "out" conformation.
四环素类（TCs）是一类重要的抗生素，面临着一种新兴的新耐药机制——酶失活的威胁。这些 TC 失活酶，也称为四环素降解酶（TDases），可使所有已知的 TC 抗生素失活，包括最后手段的药物。由 TDase 抑制剂和 TC 抗生素组成的联合疗法是克服这种类型抗生素耐药性的一种有吸引力的策略。在这里，我们报告了从脱水四环素（aTC）衍生的双功能 TDase 抑制剂的基于结构的设计、合成和评估。通过在 aTC D 环的 C9 位置附加烟酰胺类似物，我们生成了双底物 TDase 抑制剂。双底物抑制剂通过跨越 TC 和假定的 NADPH 结合口袋，与 TDases 进行了扩展相互作用。这同时阻止了 TC 的结合和 NADPH 对 FAD 的还原，同时将 TDases“锁定”在非生产性 FAD“外”构象中。
