Hansen Mette R, Jakobsen Tim H, Bang Claus G, Cohrt Anders Emil, Hansen Casper L, Clausen Janie W, Le Quement Sebastian T, Tolker-Nielsen Tim, Givskov Michael, Nielsen Thomas E
Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
Costerton Biofilm Center, Department of International Health, Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Bioorg Med Chem. 2015 Apr 1;23(7):1638-50. doi: 10.1016/j.bmc.2015.01.038. Epub 2015 Jan 31.
In an attempt to devise new antimicrobial treatments for biofilm infections, the bacterial cell-cell communication system termed quorum sensing has emerged as an attractive target. It has proven possible to intercept the communication system by synthetic non-native ligands and thereby lower the pathogenesis and antibiotic tolerance of a bacterial biofilm. To identify the structural elements important for antagonistic or agonistic activity against the Pseudomonas aeruginosa LasR protein, we report the synthesis and screening of new triazole-containing mimics of natural N-acyl homoserine lactones. A series of azide- and alkyne-containing homoserine lactone building blocks was used to prepare an expanded set of 123 homoserine lactone analogues through a combination of solution- and solid-phase synthesis methods. The resulting compounds were subjected to cell-based quorum sensing screening assays, thereby revealing several bioactive compounds, including 13 compounds with antagonistic activity and 9 compounds with agonistic activity.
为了设计出针对生物膜感染的新型抗菌治疗方法，被称为群体感应的细菌细胞间通讯系统已成为一个有吸引力的靶点。事实证明，通过合成非天然配体来阻断该通讯系统，从而降低细菌生物膜的致病性和抗生素耐受性是可行的。为了确定对铜绿假单胞菌LasR蛋白具有拮抗或激动活性的重要结构元件，我们报告了新型含三唑的天然N-酰基高丝氨酸内酯模拟物的合成及筛选。一系列含叠氮化物和炔烃的高丝氨酸内酯构建块通过溶液相和固相结合的合成方法用于制备123种扩展的高丝氨酸内酯类似物。将所得化合物进行基于细胞的群体感应筛选试验，从而发现了几种生物活性化合物，包括13种具有拮抗活性的化合物和9种具有激动活性的化合物。
