Small molecule DnaK modulators targeting the beta-domain.

The molecular chaperone DnaK is essential for the survival of bacterial pathogens in the hostile environment of the host. Hence, it is in principle a promising target for drug design but for which no current inhibitors are available apart from certain antimicrobial peptides. To this end, we have screened libraries of small molecules for their ability to interact with the substrate-binding domain of DnaK. The most promising hit from the screen was synthesized and along with its analogs subjected to further assays to determine their binding affinity and ability to interfere with bacterial growth. This work resulted in the identification of a number of compounds that bind with submicromolar affinity and capable of inhibiting Yersinia pseudotuberculosis growth more effectively than the previously characterized peptides.