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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI098091-02
Application #
8416313
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Alexander, William A
Project Start
2012-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$292,500
Indirect Cost
$142,500
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037