Virtual screening of chemical libraries into the structure of PknB shows a family of compounds have appreciable predicted binding energy. The scatter plot shows the library compound predicted binding free energy and aminofurazan family compounds are indicated with colored points. The core structure is shown for the family. Variations at the R1 and R2 positions were found to affect binding in a biochemical assay, corresponding to the predicted trend.
A ligand plot of GSK690693 interactions with PknB highlights several interactions. Hydrophobic residues are labeled in black with red hashes corresponding to red hashes around atoms in the ligand responsible for the interaction. Hydrogen bonds and corresponding donor or acceptor residues are labeled in green with distances in angstroms indicated. Hydrogen bonding residues are shown in purple sticks and GSK690693 is shown in cyan sticks.
Aminofurazans potentiate b-lactams in broth culture against resistant bacteria. Aminofurazans were tested against M. smegmatis and N. asteroides with (+) and without (+) a b‑lactam. Microbiologic IC50 values ranged from 3 µM to greater than 100 µM (ineffective). **** denotes p < 0.0001
GSK690693 also potentiates the inhibitory action of ceftriaxone in a dose-dependent manner against pathogenic Listeria monocytogenes. Growth curves of WT L. monocytogenes grown in the presence of 2.5 µg/mL ceftriaxone and increasing concentrations (µM) of GSK690693.