Towards Gram-negative antivirulence drugs: New inhibitors of HldE kinase

Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses. Development of a biochemical assay suitable for high-throughput screening allowed the discovery of inhibitors 1 and 2 of HldE kinase. Study of the structure–activity relationship of this series of inhibitors led to highly potent compounds.

Discovery of new inhibitors of HldE kinase by high throughput screening and structure–activity relationship optimization provided a promising lead series for the development of new Gram-negative antimicrobial agents.Figure optionsDownload as PowerPoint slide