Discovery of Prenyltransferase Inhibitors with In Vitro and In Vivo Antibacterial Activity
Discovery of Prenyltransferase Inhibitors with In Vitro and In Vivo Antibacterial Activity
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具有体外和体内抗菌活性的异戊二烯转移酶抑制剂的发现
DOI：
10.1021/acsinfecdis.0c00472
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发表时间：
2020
影响因子：
5.3
通讯作者：
Feng Xinxin
中科院分区：
文献类型：
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作者：
Song Junfeng;Malwal Satish R.;Baig Noman;Schurig-Briccio Lici A.;Gao Zijun;Vaidya Girija S.;Yang Kailing;Abutaleb Nader S.;Seleem Mohamed N.;Gennis Robert B.;Pogorelov Taras V;Oldfield Eric;Feng Xinxin
顺式异戊二烯基转移酶如十一异戊二烯基二磷酸合酶（UPPS）和十异戊二烯基二磷酸合酶（DPPS）是细菌中的必需酶，并且参与细胞壁生物合成。UPPS和DPPS在人类基因组中不存在，因此它们作为抗生素开发的靶点很有意义。本研究从美国国家癌症研究所Diversity Set V中筛选出750个化合物，筛选出17个化合物，并利用剂量-反应曲线测定了它们的IC 50。测试化合物对一组细菌的生长抑制、在金黄色葡萄球菌/秀丽隐杆线虫模型中的体内活性以及哺乳动物细胞毒性。最具活性的DPPS抑制剂是二羧酸氧化还原醛（化合物10），其也抑制十一异戊二烯基二磷酸合酶（UPPS）以及法呢基二磷酸脱氢酶。金黄色葡萄球菌、艰难梭菌、炭疽芽孢杆菌和枯草芽孢杆菌的IC 50增加了3.4倍。我们发现，10也是一个弱质子载体解偶联剂，导致的想法，它的目标都类异戊二烯生物合成和质子动力。在一个。金黄色葡萄球菌/C. elegans在活体模型中，10个减少了S.金黄色葡萄球菌比氨苄青霉素有效3倍。
Cis-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 ofMycobacterium tuberculosisDPPS and found 17 hits, and then IC50s were determined using dose–response curves. Compounds were tested for growth inhibition against a panel of bacteria, forin vivoactivity in aStaphylococcus aureus/Caenorhabditis elegansmodel, and for mammalian cell toxicity. The most active DPPS inhibitor was the dicarboxylic acid redoxal (compound10), which also inhibited undecaprenyl diphosphate synthase (UPPS) as well as farnesyl diphosphate synthase.10was active againstS. aureus,Clostridiodes difficile,Bacillus anthracisSterne, andBacillus subtilis, and there was a 3.4-fold increase in IC50on addition of a rescue agent, undecaprenyl monophosphate. We found that10was also a weak protonophore uncoupler, leading to the idea that it targets both isoprenoid biosynthesis and the proton motive force. In anS. aureus/C. elegans in vivomodel,10reduced theS. aureusburden 3 times more effectively than did ampicillin.