Abstract Description

Protein homeostasis (proteostasis) describes the combined cellular processes that regulate the synthesis, folding and turnover of proteins in the cell. Proteostasis is essential for cell survival and the proteostatic load increases with cellular stress. Paradoxically, the proteostasis machinery, particularly molecular chaperones, can also be co-opted by pathogens to support and progress disease. In the case of infectious diseases, both host and pathogen molecular chaperones are required for infection, dissemination and drug resistance. This means that molecular chaperones are potential drug targets for treatment of infectious disease. However, molecular chaperones are often considered undruggable due to concerns around selectively and targeting systems that rely on protein-protein interactions rather than enzyme activity. Using the examples of tuberculosis and the viral-associated malignancy Kaposi sarcoma, we demonstrate the critical role of the Hsp70-Hsp90 complex to infection using a range of in vitro and in vivo models. Despite high levels of sequence and structural conservation, selective inhibition of bacterial Hsp70 is possible. Inhibition is antibacterial and can re-sensitise resistant strains to existing antibiotics. In the case of Kaposi sarcoma, inhibition of protein-protein interactions in the Hsp90 complex is sufficient to prevent viral replication without significantly impacting cell viability. Taken together, these data demonstrate that molecular chaperones are valid targets for infection, but development of effective therapeutic strategies requires approaches specifically tailored to context and underpinned by mechanistic understanding of chaperone function.