Research

CURRENT PROJECTS

Helicobacter pylori is a bacterial pathogen that colonizes the human stomach and causes gastritis, ulcers, and stomach cancer. The health burden caused by this pathogen is particularly large as it affects about half of the world's population, and up to 100% infection rates in some developing regions. H. pylori resists the robust inflammation response and bursts of reactive oxygen species, including HOCl (bleach), from the immune cells. Our collaborators have reported that HOCl, a strong oxidant, results in a H. pylori chemoattractant response – a surprising observation, and have localized the cause of this response on an oxidation event within a chemoreceptor zinc binding (CZB) core in the highly expressed transducer-like protein D (TlpD) cytoplasmic chemoreceptor. Of note, the unique oxidation mechanism, which occurs at the Zn-bound thiolate sulfur has not been previously explored in the literature, and isolation of reactive intermediates along the oxidation pathway have proven elusive via spectroscopic or crystallographic tools. My research program is investigating the mechanism of this oxidation process using quantum chemical computations, and elucidating the role of the CZB core in activating the thiolate toward selective oxidation via HOCl (bleach). Understanding this mechanism, which is hypothesized to cause the downstream H. pylori response to the HOCl oxidant, will contribute to the rational design of therapeutic approaches to this persistent pathogen.

Nitrogen-containing sulfur(VI) compounds such as suflonamides, sulfamides, and sulfamates represent nearly 27% of the sulfur-based US Food and Drug Administration approved drugs. Drugs containing these motifs (i.e., two S=O double bonds, one S-O single bonds architecture) share similar physicochemical and bioactivity profiles. Since the earliest 20th century, the route to these compounds have been via either oxidation of thiols or via nucleophilic substitution of sulfur(VI) chloride precursors. The former requires harsh conditions incompatible with highly functionalized precursors, and precluding late-stage natural products derivatization. The latter, while widely used, requires the use of reactive sulfur (VI) precursors that suffer from thermodynamic instability, prone to redox reactions, and degradation via elimination pathways. Sulfur (VI) fluorides have recently gained popularity as alternative precursors to this e nitrogen containing sulfur(VI) compounds due to their high thermodynamic stability, resistance to redox reactions, and exclusive reactivity at the sulfur atom. Modes in which to activate sulfur(VI) fluorides, via Sulfur-Fluorine Exchange (SuFEx) reactions, have gained significant interests. Our collaborator has recently reported activation of these compounds using the Lewis acidic calcium bistriflimide (Ca(NTf2)2) salts. While successful, the role of the calcium salt in the reaction is unknown. Furthermore, reaction requires stoichiometric amount of calcium salt, precluding catalysis. My research program is investigating (i) the mechanism of the calcium triflimide mediated activation of sulfur(VI) fluorides toward nitrogen-containing sulfur(VI) fluorides, (ii) the role of stoichiometric calcium salt in the reaction, and (iii) alternate pathways that promotes more efficient catalysis.