Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section , University of Pavia , Viale Taramelli 12 , 27100 Pavia , Italy.
Medicinal Chemistry , Taros Chemicals GmbH & Co. KG , Emil-Figge-Straße 76a , 44227 Dortmund , Germany.
J Med Chem. 2019 Mar 14;62(5):2720-2737. doi: 10.1021/acs.jmedchem.9b00025. Epub 2019 Mar 4.
Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell-cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. ( S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as ( S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC ranging between 100 μM and 500 μM) encouraging further exploration of novel analogues as potential new antimicrobials.
抗生素耐药性对全球公共卫生构成持续威胁，是整个社会的巨大负担。在过去十年中，干扰细菌群体感应（QS）（即细胞间通讯）机制已被广泛研究作为开发下一代抗菌药物的有效治疗方法。（S）-4,5-二羟基-2,3-戊二酮，通常称为（S）-DPD，是一种调节革兰氏阴性和革兰氏阳性细菌中 QS 的小分子信号分子，由 LsrK 磷酸化，所得的磷酸-DPD 激活 QS。我们设计并制备了一组由五个不同支架组成的 DPD 衍生物文库，并在 QS 干扰的背景下评估了它们对 LsrK 的抑制作用。SAR 研究突出了吡唑基部分是抑制 LsrK 的必需结构元素。特别地，发现四种化合物对 LsrK 具有微摩尔抑制作用（IC 介于 100 μM 和 500 μM 之间），这鼓励进一步探索新型类似物作为潜在的新型抗菌药物。
