Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors.
Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors.
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DOI：
10.1021/acsinfecdis.6b00148
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发表时间：
2017-02
影响因子：
5.3
通讯作者：
Claire E. Weston;Andreas Krämer;Félix Colin;Özkan Yildiz;M. Baud;F. Meyer‐Almes;M. Fuchter
中科院分区：
文献类型：
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作者：
Claire E. Weston;Andreas Krämer;Félix Colin;Özkan Yildiz;M. Baud;F. Meyer‐Almes;M. Fuchter
光药理学药物具有光依赖性生物活性，在开发新的抗菌药物/模式方面具有潜力。偕胺水解酶与众所周知的人类组蛋白去乙酰化酶（hdac）同源，存在于细菌中，包括导致大量医院获得性感染和死亡的耐药生物。我们报道了这些酶的光药理学抑制剂，使用两类嵌入抑制剂药效团的光开关：偶氮苯和芳基唑。尽管这两类抑制剂对靶酶都表现出优异的抑制活性（nM IC50值），并且对可切换的E-和z -异构体形式具有不同的活性，但芳唑类抑制剂表现出更好的内在光开关性能（更完全的开关，z -异构体的热寿命更长）。我们还报道了与细菌组蛋白去乙酰酶样氨基水解酶（HDAHs）结合的偶氮苯和芳唑唑抑制剂的e-异构体的蛋白质配体晶体结构。这些结构不仅揭示了抑制剂结合的重要相互作用，而且揭示了两种光开关抑制剂之间的构象差异。因此，我们的数据可能为设计针对HDAC超家族的改进光药理学药物铺平道路。
Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well-known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital-acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitches embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles. Although both classes of inhibitor show excellent inhibitory activity (nM IC50 values) of the target enzymes and promising differential activity of the switchable E- and Z-isomeric forms, the arylazopyrazoles exhibit better intrinsic photoswitch performance (more complete switching, longer thermal lifetime of the Z-isomer). We also report protein-ligand crystal structures of the E-isomers of both an azobenzene and an arylazopyrazole inhibitor, bound to bacterial histone deacetylase-like amidohydrolases (HDAHs). These structures not only uncover interactions important for inhibitor binding but also reveal conformational differences between the two photoswitch inhibitor classes. As such, our data may pave the way for the design of improved photopharmacological agents targeting the HDAC superfamily.