Molecular basis of pathogen-host interactions A wide range of Gram negative bacteria, including important plant, animal and human pathogens have evolved sophisticated secretion systems that allow bacteria to inject a specific set of proteins collectively called "effectors" inside their eukaryotic hosts. Once inside the host cell, effectors engage a diverse range of eukaryotic targets and systems to ensure successful infection and effectual immune system regulation. Unveiling the molecular function of bacterial effectors will greatly advance our understanding of pathogenesis and can lead to uncovering of novel eukaryotic cell biology pathways. However, this process is dampened by little to no sequence similarity between effectors and functionally characterised proteins, which does not allow confident prediction of effector function, leaving large portion of these proteins uncharacterized. We use 3D structure determination as segue into characterization of the function of variety effector proteins. This approach combined with biochemical and in vivo assays allowed us to unveil the function of several large families of effector proteins involved in hijacking of host ubiquitination system.
Clinical and emerging antibiotic resistance elements Antibiotic resistance is a serious and growing health concern. Many clinically-relevant species, particularly so-called ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species evolve or acquire mechanisms rendering antibiotics ineffective.
In our lab, we are carrying out several structure-function and inhibition studies of proteins involved in clinically important and emerging antibiotic resistance mechanisms. Specifically, we pursue characterization of bacterial enzymes conferring resistance to the glycopeptide drug of last resort vancomycin, aminoglycosides, streptogramin compounds and other antibiotics. We use X-ray crystallography as our primary tool to produce detailed insights into molecular structure of these resistance elements and use this information to guide design of potent inhibitory scaffolds that can be used as antibiotic adjuvants for combined antimicrobial therapy.
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