Small molecule modulation of HSP60/10 chaperonin systems: More common than previously thought?

Abstract

All living organisms contain a unique class of molecular chaperones called 60 kilodalton heat shock proteins (HSP60, also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, one has consistently proven essential in the micro-organisms thus far evaluated. Accordingly, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African Sleeping Sickness (caused by Trypanosoma brucei), drug-resistant bacterial infections (particularly Methicillin-resistant Staphylococcus aureus – MRSA), and tuberculosis. Intriguingly, our studies found that three known antibiotics – suramin, closantel, and rafoxanide – were potent inhibitors of bacterial GroEL and human HSP60. These findings prompted us to explore what other known drugs, natural products, and bioactive molecules might also inhibit these chaperonin systems. Initial high-throughput screening of 3,680 known drugs, natural products, and bioactive molecules identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than originally appreciated. Future studies to determine the extent to which GroEL and HSP60 inhibition contributes to the function of these known drugs, natural products, and bioactive molecules in vivo are required.