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Targeting Bacterial Phosphatases for Novel Anti-Bacterial Agents

Investigators
Pellecchia, Maurizio
Institutions
Sanford-Burnham Medical Research Institute
Start date
2012
End date
2014
Objective
Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica use a number of toxins to evade the immune system one of which is the protein tyrosine phosphatase YopH. Following infection, YopH is injected into phagocytic cell resulting in the disruption of focal adhesions, and inhibition of integrin-mediated bacterial phagocytosis, both of which are highly dependent on tyrosine phosphorylation. Hence, targeting YopH against these pathogens represents a sensible yet underexplored strategy for the development of novel anti-bacterial adjuvant to antibiotics.

Our hypothesis is that effective small-molecule inhibitors f YopH would render YopH- paralyzed immune cells immediately functional again hence able to initiate both innate and adaptive immune responses. Hence, the molecules that will arise from this pilot study may result very useful not only as potential therapeutics, but also in probing at the cellular level the mechanisms of toxin induced cell death and inhibition of phagocytosis, common to several other pathogens.

More information
Public Health Relevance:
We envision that inhibitors of a critical bacterial toxin may be valuable for treating Yersinia pestis, Salmonella enterica, and Yersinia enterocolitica infections, as a supportive complement to antibiotics. This pilot study will provide critical proof of concept for this innovative approach.
Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project source
View this project
Project number
1R21AI098091-01A1
Categories
Salmonella
Bacterial Pathogens
Natural Toxins
Yersinia