Professor
Email: gutheilw@umkc.edu
Our research is focused on the identification of new antibacterial agents and synergistic antibacterial agent combinations, antibacterial agents targeting bacterial cell wall biosynthesis, the enzyme targets of these agents, and the characterization of resistance to antibacterial agents. One of our key strengths is in the area of analytical biochemistry, and I am director of the UMKC Drug Discovery and Metabolomics LC-MS Shared Instrumentation Resource. We have developed LC-MS/MS analytical methods for all of the cytoplasmic intermediates in the bacterial cell wall biosynthesis pathway, as well as of all DNA and RNA component nucleosides and nucleotides. Our recent acquisition of a QToF instrument now provides for high sensitivity analytical studies, and untargeted metabolomics studies. We are using these analytical methods and instruments to explore in detail how different antibiotics affect this pathway in several antibiotic sensitive and resistant bacterial pathogens, and to reveal mechanisms of actions of novel antibacterial agents. We have initiated a library-screening program for new antibacterial agents. As part of this effort, we have performed en masse microsomal metabolism of these (FDA approved drug) libraries. A comparative screen of the un-met (UM) library with the pre-met (PM) library allows agents with active metabolites to be identified. Such a screen can be further enhanced by combining with a -/+ other antibiotic screen. The additional “dimensions” of such an approach allows intrinsically active agents to be identified, agents with active metabolites to be identified, and agents acting synergistically or antagonistically with the other library compounds (drugs) to be identified – all in a single screen. Such “information rich” screening seems to have considerable promise for addressing the problem of antimicrobial resistance and is the topic of this application.
Keywords: Chemical Biology
