Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, and Department of Chemistry, Hunan University, Changsha 410082, China.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Infect Dis. 2020 Nov 13;6(11):2979-2993. doi: 10.1021/acsinfecdis.0c00472. Epub 2020 Oct 21.
-prenyltransferases such as undecaprenyl diphosphate synthase (UPPS) and decaprenyl diphosphate synthase (DPPS) are essential enzymes in bacteria and are involved in cell wall biosynthesis. UPPS and DPPS are absent in the human genome, so they are of interest as targets for antibiotic development. Here, we screened a library of 750 compounds from National Cancer Institute Diversity Set V for the inhibition of DPPS and found 17 hits, and then ICs were determined using dose-response curves. Compounds were tested for growth inhibition against a panel of bacteria, for activity in a / model, and for mammalian cell toxicity. The most active DPPS inhibitor was the dicarboxylic acid redoxal (compound ), which also inhibited undecaprenyl diphosphate synthase (UPPS) as well as farnesyl diphosphate synthase. was active against , , Sterne, and , and there was a 3.4-fold increase in IC on addition of a rescue agent, undecaprenyl monophosphate. We found that was also a weak protonophore uncoupler, leading to the idea that it targets both isoprenoid biosynthesis and the proton motive force. In an / model, reduced the burden 3 times more effectively than did ampicillin.
香叶基焦磷酸合酶（UPPS）和法呢基焦磷酸合酶（DPPS）等prenyltransferases 是细菌中必不可少的酶，参与细胞壁生物合成。UPPS 和 DPPS 不存在于人类基因组中，因此它们是抗生素开发的有价值的靶点。在这里，我们筛选了 NCI 多样性集 V 中的 750 种化合物文库，以抑制 DPPS，并发现了 17 个阳性化合物，然后使用剂量反应曲线确定 IC。测试化合物对一系列细菌的生长抑制作用、在 / 模型中的活性以及对哺乳动物细胞的毒性。最有效的 DPPS 抑制剂是二羧酸氧化还原化合物（ ），它还抑制了香叶基焦磷酸合酶（UPPS）和法呢基焦磷酸合酶。对 、 、 、Sterne 和 有效，加入救援剂单磷酸十一碳烯焦磷酸后，IC 增加了 3.4 倍。我们发现 也是一种弱质子载体解偶联剂，这表明它靶向异戊二烯生物合成和质子动力。在 / 模型中， 比氨苄西林更有效地减少 3 倍的负担。
