Our current research projects:
1. Achromobacter xylosoxidans (Ax) infection
We use collections of clinical Ax isolates obtained from individual patients over the course of chronic infection to investigate how the pathogen adapts within the host.
- How does Ax develop multidrug resistance? Several longitudinal isolate series show dramatic changes in antibiotic resistance over the course of infection. We use comparative genomics to identify genetic changes associated with the emergence of antibiotic resistance and dissect the molecular mechanisms underlying these changes.
- How Ax adapt to the host during prolonged infection? Ax virulence changes substantially between isolates collected from early and late stages of infection. Using comparative genomics together with immunological approaches, we identify genetic changes that occur during chronic infection and investigate how these changes affect bacterial virulence, host interactions, and long-term persistence.
2. Develop inhibitors of bacterial phospholipases
Bacterial phospholipases contribute to virulence in a number of important pathogens and represent potential targets for anti-virulence therapy. We use the P. aeruginosa T3SS effector ExoU as a model bacterial phospholipase to identify and develop inhibitors of bacterial phospholipases. Our goal is to develop strategies that interfere with bacterial virulence and pathogenicity without directly targeting bacterial survival.
P. aeruginosa manipulates the host by injecting its T3SS substrates into host cells. The effector ExoU has the strongest impact on host pathology of all Pseudomonas T3SS effector proteins. ExoU has phospholipase A2 activity that disrupts the host cell membrane and promotes inflammation when ExoU is activated inside the host cell. Delaying expression of ExoU can increase the survival of infected mice. ExoU homologs have been found and validated in a number of bacterial pathogens. Our current efforts include SAR study of ExoU inhibitors identified from molecular docking.
Funding
We are grateful for funding by the NIH and Virginia Tech
