She earned her M.S. degree in Chemistry in 2004 and her Ph.D. degree in Chemistry in 2007. Her Ph.D. thesis work, under the guidance of Professor Seth M. Cohen, consisted of examining novel zinc-specific chelators for incorporation into inhibitors of matrix metalloproteinases. In 2008 she started her NIH-funded postdoctoral research with Professor David P. Giedroc, studying zinc homeostasis in Streptococcus pneumoniae. David Giedroc graduated from the Pennsylvania State University in 1980 with his B.S. degree in Biochemistry. After a brief stint in Joseph Villafranca's group at Penn State, he earned his Ph.D. degree in Biochemistry at Vanderbilt University in 1984, where he worked with David Puett on the calcium sensor calmodulin. From 1984 to 1988, he was an NIH postdoctoral fellow in the late Joseph E. Coleman's laboratory at Yale University, where he worked on zinc-finger DNA binding proteins. From 1988 to 2007, he was a member of the faculty in the Department of Biochemistry and Biophysics at Texas A&M University. He is now Professor of Chemistry at Indiana University, where he continues his studies of metalloregulatory proteins and viral RNA structure, folding, and function.

Streptococcus pneumoniae D39 AdcR (adhesin competence repressor) is the first metal-sensing member of the MarR (multiple antibiotic resistance repressor) family to be characterized. Expression profiling with a ΔadcR strain grown in liquid culture (brain heart infusion; BHI) under microaerobic conditions reveals upregulation of 13 genes including adcR and adcCBA, encoding a high affinity ABC uptake system for zinc, and genes encoding cell-surface zinc-binding pneumococcal histidine triad (Pht) proteins and AdcAII (Lmb, laminin binding). The ΔadcR, H108Q and H112Q adcR mutant allelic strains grown in 0.2 mM Zn(II) exhibit a slow-growth phenotype and a ≈2-fold increase in cell-associated Zn(II). Apo-and Zn(II)-bound AdcR are homodimers in solution and binding to a 28-mer DNA containing an adc operator is strongly stimulated by Zn(II) with K DNA-Zn = 2.4 ×10 8 M −1 (pH 6.0, 0.2 M NaCl, 25 °C). AdcR binds two Zn(II) per dimer, with step-wise Zn(II) affinities K Zn1 and K Zn2 of ≥10 9 M −1 at pH 6.0 and ≥10 12 M −1 at pH 8.0. X-ray absorption spectroscopy (XAS) of the high affinity site reveals a pentacoordinate N/O complex and no cysteine coordination, the latter finding corroborated by wild-type-like functional properties of C30A AdcR. Alanine substitution of conserved residues His42 in the DNA binding domain, and His108 and His112 in the C-terminal regulatory domain, abolish high affinity Zn(II) binding and greatly reduce Zn(II)-activated binding to DNA. NMR studies reveal that these mutants adopt the same folded conformation as dimeric wild-type apo AdcR, but fail to conformationally switch upon Zn(II) binding. These studies clearly identify His42, His108 and H112 as metalloregulatory zinc ligands in S. pneumoniae AdcR.

ICP-MS analysis of Streptococcus pneumoniae reveals a high cell-associated Mn(II) concentration that is comparable to that of Zn(II). Stressing these cells with 100–200 μM Zn(II) leads to a slow-growth phenotype and a total Mn(II) concentration that is reduced, with no decrease of other metal ions. Supplementation of the growth media with as little as 10 μM Mn(II) fully restores the growth defect and cell-associated Mn(II) to normal levels. DNA microarray analysis reveals that zinc stress induces the expected upregulation of czcD (encoding a zinc effluxer), but also a pleiotropic transcriptional response suggestive of mild cell wall stress. Genes encoding a nitric oxide (NO) detoxification system (nmlR) and the Mn(II) uptake system (psaBCA) are also induced. We conclude that Zn(II) toxicity results in a cytoplasmic Mn(II) deficiency, possibly caused by competition at the Mn(II) uptake transporter protein PsaA.

In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs) several new zinc-binding groups (ZBGs) based on pyridine-derived or aza-macrocycle chelators have been examined. Fluorescence-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-1, MMP-3, and anthrax lethal factor (LF). Many of these ligands were found to be remarkably potent, with IC50 values as much as 185-fold lower than that found for acetohydroxamic acid. These ligands are proposed to be more selective "warheads" for the inhibition of metalloenzymes that contain Zn2+ versus other metal ions at their active site.