Exploiting the GroEL/ES chaperonin system as a mechanistically novel antimicrobial target.
The GroEL/ES chaperonin system is a remarkable example of a diverse class of specialized proteins, called molecular chaperones, which help other proteins fold to their native states. As GroEL/ES is ubiquitous, essential, and highly conserved across bacteria, targeting of this chaperonin system represents an exciting strategy for developing mechanistically unique antibacterials. Preliminary studies have indicated that many of our GroEL/ES chaperonin inhibitors also halt the growth of medically-relevant Gram-positive bacteria such as S. aureus. Investigations are focused on developing cell-based models to validate the GroEL/ES system as the primary target for antibacterial activity; investigating the selectivity of these molecules for bacterial GroEL relative to the human HSP60 homologue to gauge potential host cell toxicity concerns, and; evaluating lead antimicrobials that are well tolerated by mammalian cell lines for their in vivo efficacy in mouse infection models. We are also investigating the applicability of this strategy for targeting pathogens other than bacteria and have found that Leishmania promastigotes and axenic amastigotes are susceptible to some of these compounds.
Modulation of molecular chaperones and protein homeostasis for the development of neurodegeneration and oncology therapeutics.
It is reasonable to believe that subsets of the recently identified GroEL/ES inhibitors might also have modulatory effects on the human homologue, HSP60/10. This poses an exciting possibility for developing chemical probes to study the function of the mammalian chaperonin system, especially in the context of HSP60/10-associated disease states in various cancers (e.g. breast) and neurodegenerative disorders (e.g. hereditary spastic paraplegia). Since a cancer drug that targets the HSP60/10 chaperonin system has yet to be developed, and there are currently no therapeutics that address the underlying biogenesis of hereditary spastic paraplegia (treatment primarily consists of symptomatic medical management), this area of research offers new and exciting opportunities for the development of life-saving treatments for these diseases.
Development of Mycobacteria tuberculosis protein tyrosine phosphatase B inhibitors.
Protein tyrosine phosphatase B (PtpB) is a virulence factor that M. tuberculosis secretes into host macrophages to disrupt signaling pathways and inhibit apoptosis, resulting in increased intracellular reservoirs of the pathogen. PtpB is an intriguing target for anti-tuberculosis therapeutic development because the enzyme functions outside the bacterium. Preliminary evaluation in phosphatase activity assays demonstrates that one of our lead GroEL/ES inhibitor classes is also a promising initial hit for PtpB inhibition. We are optimizing this scaffold for phosphatase inhibition in biochemical assays and evaluating lead analogues for their efficacy in macrophage infection experiments. While SAR appears somewhat divergent, an enticing possibility exists for development of these compounds as dual inhibitors of both GroEL/ES and PtpB in M. tuberculosis
