期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 9, 页码 4165-4175出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00289
关键词
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资金
- Swedish Research Council
- ERC [260764-RNAntibiotics]
- Knut and Alice Wallenberg Foundation
- Goran Gustafsson Foundation
- Swedish Foundation for Strategic Research
- Kempe Foundation
Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein tunnel as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix turn helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.
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