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.
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.
|Bottini, Angel; Wu, Bainan; Barile, Elisa et al. (2016) High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH. ChemMedChem 11:919-27|
|Bottini, Angel; De, Surya K; Wu, Bainan et al. (2015) Targeting Influenza A Virus RNA Promoter. Chem Biol Drug Des 86:663-73|
|Bottini, Angel; De, Surya K; Baaten, Bas J G et al. (2012) Identification of small molecules that interfere with H1N1 influenza A viral replication. ChemMedChem 7:2227-35|