Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study

被引：60

作者：

Lepri, Susan ^{[1
]}

Buonerba, Federica ^{[1
]}

Goracci, Laura ^{[1
]}

Velilla, Irene ^{[1
]}

Ruzziconi, Renzo ^{[1
]}

Schindler, Bryan D. ^{[2
]}

Seo, Susan M. ^{[2
]}

Kaatz, Glenn W. ^{[2
,3
]}

Cruciani, Gabriele ^{[1
]}

机构：

[1] Univ Perugia, Dept Chem Biol & Biotechnol, I-06123 Perugia, Italy

[2] John D Dingell Dept Vet Affairs Med Ctr, Detroit, MI 48201 USA

[3] Wayne State Univ, Sch Med, Div Infect Dis, Dept Internal Med, Detroit, MI 48201 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 03期

关键词：

NORA EFFLUX PUMP; STAPHYLOCOCCUS-AUREUS; PK(A) PREDICTION; INHIBITORS; DERIVATIVES; METAL; DISCOVERY; DESIGN; AGENT; AZIDE;

D O I：

10.1021/acs.jmedchem.5b01219

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 mu M proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.

引用

页码：867 / 891

页数：25

共 51 条

[1] Structure-activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus [J].