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

页码：98 / 109

页数：12

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