Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.
Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.
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DOI：
10.1021/acs.jmedchem.2c01629
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发表时间：
2023-03
影响因子：
7.3
通讯作者：
Emily E Williford;Caitlin M DeAngelo;Kevin S. Blake;H. Kumar;Kendrick K Lam;Katherine V Jones;N. Tolia;G. Dantas;T. Wencewicz
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文献类型：
--
作者：
Emily E Williford;Caitlin M DeAngelo;Kevin S. Blake;H. Kumar;Kendrick K Lam;Katherine V Jones;N. Tolia;G. Dantas;T. Wencewicz
四环素类抗生素是一类重要的抗生素，目前正受到一种新的耐药机制--酶失活的威胁。这些TC失活酶，也称为四环素破坏酶（TDases），包括所有已知的TC抗生素，包括最后的药物。由TDase抑制剂和TC抗生素组成的联合治疗代表了克服这种类型的抗生素耐药性的有吸引力的策略。在这里，我们报告了基于结构的设计，合成和评价的双功能TDase抑制剂来自脱水四环素（aTC）。通过将烟酰胺等排体附加到aTC D-环的C9位置，我们产生了双底物TDase抑制剂。双底物抑制剂通过跨越TC和假定的NADPH结合口袋而与TDases具有扩展的相互作用。这同时阻断TC结合和NADPH对FAD的还原，同时将TDases“锁定”在非生产性FAD“外”构象。
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.