Lynn Zechiedrich, Ph.D.
Department of Molecular Virology and Microbiology
Department of Biochemistry and Molecular Biology
Kyle and Josephine Morrow Chair in Molecular Virology and Microbiology
Fluoroquinolone Resistance in E. coli
Fluoroquinolones are among the most potent, widely prescribed, broad-spectrum oral antibiotics. Quinolones kill bacteria by targeting the two type-2 topoisomerases, gyrase and topoisomerase IV. These essential enzymes pass DNA strands through each other and are required for DNA replication, recombination, transcription, chromosome segregation, and maintenance of DNA supercoiling levels. Quinolones stabilize the normal, transient topoisomerase-DNA cleavage intermediate. With a mechanism that is not well understood, DNA tracking by processes such as replication or transcription collide with the drug-stabilized topoisomerase-DNA adducts to cause cell death.
To reach their cellular targets, drugs must first penetrate the defense system of the bacterial cell. Not only are cells well-equipped to withstand treatment with drugs, but it has become increasingly clear that bacteria undergo genetic alteration to become resistant to drugs. Although drug resistant bacteria are one of the most critical problems facing the medical community today, surprisingly little is known about how cells resist drugs. Therefore, the goal of our research is to determine how the model system Escherichia coli respond to and resist treatment with the quinolone antibiotics. Ultimately, our results may be used to design better chemotherapeutics to help prevent the worldwide problem of drug resistance.
DNA Topoisomerases, DNA Structure and DNA Topology
By passing DNA strands through each other, the ubiquitous topoisomerases control chromosome condensation, chromosome segregation, DNA replication, DNA transcription, and DNA recombination. Topoisomerases break and reseal DNA to modulate DNA supercoils, DNA catenanes, and DNA knots. Because of their essential roles, topoisomerases are the cellular targets for widely prescribed chemotherapeutics. The normally short-lived, broken DNA intermediate produced by topoisomerases is increased by the drugs, which causes cell death. We use biochemical, biophysical and genetic techniques to determine how topoisomerases carry out the cellular roles and how drugs block their function.
Learn more about Dr. Zechiedrich's work on the Zechiedrich Lab website.
- Randall, G. L., Zechiedrich, L., and Pettitt, B. M. (2009). In the absence of writhe, DNA relieves torsional stress with localized, sequence-dependent structural failure to preserve B-form. Nucleic Acids Res. 37, 5568-5577.
- Liu, Z., Zechiedrich, L., and Chan, H.S. (2010). Local site preference rationalizes disentangling by DNA topoisomerases. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 81, 031902.
- Liu, Z., Zechiedrich, L., and Chan, H.S. (2010). Action at hooked or twisted-hooked DNA juxtapositions rationalizes unlinking preference of type-2 topoisomerases. J. Mol. Biol. 400, 963-982.
- Zechiedrich, L. and Osheroff, N. (2010). Topoisomerase IB-DNA interactions: X marks the spot. Structure .18, 661-663.
- Zhao, N., Fogg, J.M., Zechiedrich, L., and Zu, Y. (2011). Transfection of shRNA-encoding Minivector DNA of a few hundred base pairs to regulate gene expression in lymphoma cells. Gene Ther. 18, 220-224.
- Swick, M.C., Morgan-Linnell, S.K., Carlson, K.M., and Zechiedrich, L. (2011). Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichia coli clinical isolates as a function of fluoroquinolone and multidrug resistance. Antimicrob. Agents Chemother. 55, 921-924.
- Catanese, D.J., Jr., Fogg, J.M., Schrock, D.E., II, Gilbert, B.E., and Zechiedrich, L. (2012). Supercoiled Minivectors resist shear forces associated with gene therapy delivery. Gene Ther. 19, 94-100.
- Singh, R., Swick, M.C., Ledesma, K.R., Yang, Z., Hu, M., Zechiedrich, L., and Tam, V. (2012). Temporal interplay between efflux pumps and target mutations in development of antibiotic resistance in Escherichia coli. Antimicrob. Agents Chemother. 4, 1680-1685.
- Zechiedrich, L. (2012). Editorial comment to Genome-wide transcriptome analysis of fluoroquinolone resistance in clinical isolates of Escherichia coli. Int. J. Urol. 4, 368-369.
- Fogg, J.M., Randall, G. L., Pettitt, B. M., Sumners, D.W.L., Harris, S.A., and Zechiedrich, L. (2012). Bullied no more: When and how DNA shoves proteins around. Quart. Rev. Biophys. In press.