Our research program spans a broad range of chemistry, chemical biology, microbiology, bioinorganic chemistry, cell biology and structural biology.  We probe the pathways and mechanisms of DNA/RNA repair and modification.  We work on virulence and antibiotic resistance regulation in human pathogens, and develop new antibiotics.  We study selective metal ion recognition and sensing by naturally occurring and engineered proteins.  We also explore metal-catalyzed organic transformations.

1. DNA/RNA Repair and Modification
Accumulation of genetic changes due to the presence of unrepaired DNA lesions can lead to cancer and other diseases.  One component of our research program is to develop and apply a novel chemical cross-linking technique to stabilize protein-DNA interactions in distinct states in these systems. An integrative approach uniting chemical synthesis, structural biology and biochemical/biophysical characterization is used to study these interactions in DNA/RNA repair AlkB family proteins and other DNA/RNA base repair and modification proteins.  In a related component of the research, we work on elucidating new pathways and mechanisms involved in DNA and RNA base modification with a focus on methylation and demethylation.

2. Virulence and Antibiotic Resistance Regulation in Human Pathogens
Staphylococcus aureus, Pseudomonas aeruginosa and Mycobacterium tuberculosis are human pathogens responsible for most wound and hospital-acquired infections.  The extensive use of antibiotics to treat infections has led to the emergence of high-level resistances in various strains of these pathogens.  Virulence suppression serves as an alternative strategy to effectively reduce pathogenic potential without asserting selective pressure for developing resistances.  A recent discovery in our laboratory has identified the MgrA protein as a key virulence regulator in S. aureus.  This protein belongs to the MarR family of transcriptional regulators that controls antibiotic resistance and virulence in various bacteria.  We demonstrated that the mgrA knockout strain shows a 10,000-fold reduction of virulence in vivo.  Subsequently, we discovered that oxidative stress leads to dissociation of MgrA from its promoter DNA.  Responding to S. aureus infection, the host immune system produces reactive oxygen and nitrogen species to counter the pathogen.  Our study suggests that the microorganism uses MgrA to sense the oxidative stress generated by the host and to regulate a global defensive response.  We plan to not only fully elucidate the mechanism of MgrA and its regulation pathways, but also explore strategies to suppress bacterialvirulence by tuning MgrA’s function with small molecules.  In addition, we look for new targets and novel strategies for treating bacterial infections.

3. Selective Metal Ion Recognition by Proteins
The ability to regulate essential or toxic metal ion concentrations is critical for cell survival.  Our goal is to understand how specific metal ions are recognized and regulated in biological systems.  We have been working on elucidating the mechanisms of proteins that exhibit remarkable selectivity toward metal ions such as lead(II), cadmium(II), gold(I), copper(I) and iron(II).  Some of these proteins can be converted into genetically encoded fluorescent probes for sub-cellular metal ion imaging in live cell.  We also work on engineering proteins that possess high sensitivity and selectivity toward various metal ions including actinides. 

4. Catalysis
We study the fundamental activity of metal complexes and develop new organic transformations.  Currently, our group is focusing on direct functionalization of inert C-H groups and activation of inert small molecules with metal catalysts.