Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
ACS Chem Biol. 2022 Jul 15;17(7):1890-1900. doi: 10.1021/acschembio.2c00321. Epub 2022 Jun 8.
Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant . This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
抗生素耐药性是一个全球性的重大问题，因此迫切需要具有机制新颖作用模式的新药。在这里，我们报告了基于结构的药物设计、合成以及体外和细胞系统评估，涉及能够抑制细菌唾液酸转运蛋白 SiaT 的唾液酸衍生物。我们设计并合成了 21 种唾液酸衍生物，通过热位移测定法筛选它们与 SiaT 的亲和力，并通过结合热力学、计算方法和抑制动力学研究阐明了抑制机制。与天然底物相比，亲和力高 180 倍的最有效化合物在细菌生长测定中进行了测试，并表明耐甲氧西林的细菌生长延迟。本研究代表了作为新型抗菌剂开发唾液酸摄取抑制剂的首例实例和有希望的先导化合物。
