In this project funded by the Inorganic, Bioinorganic, and Organometallic Chemistry Program of the Chemistry Division, Michael T. Ashby of the University of Oklahoma will study the reaction mechanisms of sulfur species of fundamental chemical interest that are implicated in biological antimicrobial processes. The understanding of sulfur species reactivity under physiological conditions is very limited, even though they are implicated in cellular damage processes. The information gained from these studies will find application in biological/medical fields, and such studies will also enhance fundamental knowledge of sulfur chemistry. The PI will be involved in graduate student and postdoctoral training and has a track record of broadening the participation of underrepresented groups in chemistry.
The project has focused on understanding the chemical mechanisms that involve biological reactive intermediates, mostly oxidative human defense factors, with sulfur-containing compounds. These sulfur compounds have included the amino acids cysteine and methionine as well as inorganic sulfur-containing compounds such as thiocyanate. Human inflammatory diseases frequently produce oxidative stress on host tissues. Sulfur compounds are frequently damaged during oxidative stress within cells, and therefore their oxidized derivatives are early indicators of oxidative stress. Certain human defensive peroxidase-derived molecules take advantage of the differential reactivity of sulfur compounds in human cells versus infectious cells to yield a strategy for host defense. Our research had contributed to understanding the mechanism of action of these defensive agents, that have included the oxidized derivatives of the halides (e.g., hypochlorous acids and hypobromous acid) as well as the pseudo-halide thiocyanate (hypothiocyanite). In the course of our studies, we have discovered new anti-bacterial and anti-fungal agents. We have also discovered non-enzymic and inexpensive ways of synthesizing some of these agents, thereby paving the way for their commercial applications. Furthermore, the fundamental insight we have provided into their mechanisms of action may allow future researchers the opportunity to synthesis new non-antibiotic antimicrobials (NAAM). Such research may prove key to resolving the current crisis in multi-drug antibiotic resistance. Indeed, many of the compounds we have discovered may serve as commercially important NAAM with applications in human health and agriculture.
