Chemotherapy and host immunity both impose stresses on bacterial pathogens resulting in protein aggregation. Eukaryotic Hsp104/Hsp70 and their bacterial homologs ClpB/DnaK are ATP-powered chaperones that restore toxic protein aggregates to a native folded state. DnaK is predicted to be essential in several species of mycobacteria, including the pathogen <i>M. tuberculosis </i>(Mtb), which is the infective agent of tuberculosis (TB). We and others have shown that ClpB mediates a stress response to sublethal doses of antibiotic in Mtb. Both DnaK and ClpB are potential drug targets in mycobacteria; however, their molecular partners in protein reactivation and modes of inhibition have not been thoroughly explored. We have performed small molecule high-throughput screening against mycobacterial DnaK and known cofactors, and have identified small molecule inhibitors that target allosteric sites on DnaK. In this talk, we characterize the modes of binding of these small molecules and discuss strategies to selectively target bacterial chaperones based on their mechanisms of inhibition.

Exploring new modes of inhibition of bacterial chaperones

ACS Spring Meeting 2021

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