Identification of Small Molecule Inhibitors That Block the Toxoplasma gondii Rhoptry Kinase ROP18

The protozoan parasite Toxoplasma gondii secretes a family of serine-threonine protein kinases into its host cell in order to disrupt signaling and alter immune responses. One prominent secretory effector is the rhoptry protein 18 (ROP18), a serine-threonine kinase that phosphorylates immunity related GTPases (IRGs) and hence blocks interferon gamma-mediated responses in rodent cells. Previous genetic studies show that ROP18 is a major virulence component of T. gondii strains from North and South America. Here, we implemented a high throughput screen to identify small molecule inhibitors of ROP18 in vitro and subsequently validated their specificity within infected cells. Although ROP18 was not susceptible to many kinase-directed inhibitors that affect mammalian kinases, the screen identified several sub micromolar inhibitors that belong to three chemical scaffolds: oxindoles, 6-azaquinazolines, and pyrazolopyridines. Treatment of interferon gamma-activated cells with one of these inhibitors enhanced immunity related GTPase recruitment to wild type parasites, recapitulating the defect of Δ rop18 mutant parasites, consistent with targeting ROP18 within infected cells. These compounds provide useful starting points for chemical biology experiments or as leads for therapeutic interventions designed to reduce parasite virulence

Novel compounds to treat urinary tract infection [abstract]

Urinary tract infections (UTI) affect a large proportion of the population and account for significant morbidity and high medical costs. Uropathogenic Escherichia coli (UPEC) is responsible for up to 85% of infections and a large percentage of recurrent UTI are caused by the same strain of bacteria as the initial UTI despite the antibiotic regimen; the current gold standard. The annual UTI incidence rate is 12.1% in women and 3% among men. Recurrence rates are high with women having a 25% to 44% chance of developing a second episode within 6 months of the initial UTI. Treatment of UTI like other microbial infections is exacerbated by increasing antimicrobial resistance and there is a huge unmet need for alternative therapies. Novel patented compounds such as Pilicides and Mannosides disrupt pili biogenesis and host-pathogen interaction to effectively block disease progression. Potential Areas of Applications: * Urinary tract Infection