Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

被引：19
作者：
Brindisi, Margherita [1 ,2 ]
Brogi, Simone [1 ,2 ]
Giovani, Simone [1 ,2 ]
Gemma, Sandra [1 ,2 ]
Lamponi, Stefania [1 ,2 ]
De Luca, Filomena [3 ]
Novellino, Ettore [4 ]
Campiani, Giuseppe [1 ,2 ]
Docquier, Jean-Denis [3 ]
Butini, Stefania [1 ,2 ]
机构：
[1] Univ Siena, European Res Ctr Drug Discovery & Dev NatSynDrugs, Via Aldo Moro 2, I-53100 Siena, Italy
[2] Univ Siena, Dept Biotechnol Chem & Pharm, Siena, Italy
[3] Univ Siena, Dept Med Biotechnol, Siena, Italy
[4] Univ Napoli Federico II, Dept Pharm, Naples, Italy
来源：
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2016年 / 31卷
关键词：
Antibiotic resistance; docking; metallob-lactamase; PSEUDOMONAS-AERUGINOSA; BIOCHEMICAL-CHARACTERIZATION; GENETIC ALGORITHM; CRYSTAL-STRUCTURE; VIM-2; ASPERGILLOMARASMINE; DERIVATIVES; REVEALS; DESIGN; UPDATE;
D O I：
10.3109/14756366.2016.1172575
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Metallo-beta-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to beta-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based high-throughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.
引用
收藏
页码：98 / 109
页数：12
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