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Mentor: Robert J. Kerns, PhD
Year Entered Into Program: 2009
PhD Institution: University of Iowa, 2013
My research is focused on the design and synthesis of novel quinolone-class antibiotics that will kill bacteria in the absence of ongoing protein synthesis, thus killing dormant or semi-dormant bacteria such as found with M. tuberculosis. Fluoroquinolones target DNA gyrase and topoisomerase IV enzymes in bacteria. DNA gyrase and topoisomerase IV introduce and relax supercoils in the DNA, thereby allowing access to DNA helicase to form the replication fork. This action is carried out by nicking each strand of DNA, winding or unwinding the DNA, and then ligating the strands back together. Upon binding the enzyme, the fluoroquinolone prevents DNA gyrase (or topo IV) from ligating the DNA strands. This inhibits the growth and normal function of the cell. Additionally, it has been shown that some structurally unique fluoroquinolones are able to promote chromosome fragmentation and rapidly kill bacteria, even when protein synthesis is blocked. The mechanism of this action for these select fluoroquinolones is not known. The goal of my research is to characterize the structural requirements of fluoroquinolones to facilitate chromosome fragmentation and rapidly kill cells; especially in the absence of ongoing protein synthesis. Current structure-function studies are focused on determining the structural requirements at positions N-1 and C-8 of fluoroquinolones to impart lethality in the absence of protein synthesis. Compounds from my work that have different levels of activity for killing non-replicating cells are also being used to understand the underlying mechanistic differences in how these agents act to fragment chromosomes and kill non-replicating cells.
Towle, T., Chang, I., Kerns, R., Bhanot, P.: Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites. Bioorg. Med. Chem. Lett. 23(6):1874-1877, 2013. PMID: 23395653 [PubMed - in Process]
Turecek, F., Jones, J.W., Towle, T., Panja, S., Brøndsted Nielsen, S., Hvelplund, P. and Paizs, B.: Hidden Histidine Radical Rearrangements upon Electron Transfer to Gas-Phase Peptide Ions. Experimental Evidence and Theoretical Analysis. J Am Chem Soc 130(44):14584-14596, 2008. PMID: 18847261 “PMC Journal – In Process”
Schwanz HA, Manzar A, Malik M, Towle TR, Gangqin Li, Drlica K, Kerns RJ. “Effect of quinolone structure on the killing of Escherichia coli in the presence and absence of ongoing protein synthesis.”Journal of Medicinal Chemistry. 2012. Manuscript in progress.
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