Targeting the Bacterial Chaperone System GroES/GroEL as an Antimicrobial Strategy

Abstract

Molecular chaperones assist in the refolding of newly translated, heat-denatured, or stress-denatured proteins. GroEL, along with cochaperone GroES, help to refold nearly 10 percent of the E. coli proteome. More than a dozen essential proteins rely on this chaperone system alone to maintain their appropriate structure and function. Depletion of cellular GroES/GroEL or disruption of GroES/GroEL activity results in rapid bacterial cell death. Here, we describe validation of GroES/GroEL as an actionable target using small molecules capable of inhibiting chaperone activity. GroES/GroEL from the ESKAPE pathogens, a collection of the most common healthcare-associated multidrug-resistant bacteria, were used to determine the extent to which small molecule inhibitors engage and elicit their antimicrobial activity through this chaperone system.