Lynn Zechiedrich, Ph.D.
Professor, Molecular Virology and Microbiology
Kyle and Josephine Morrow Chair in Molecular Virology and Microbiology
SCBMB Executive Committee Member
Baylor College of Medicine
B.S., Zoology, University of Arkansas (1985)
Ph.D., Biochemistry, Vanderbilt University School of Medicine (1990)
Postdoctoral Biochemistry, University of California, Berkley (1997)
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 (more). 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 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, huge gaps remain in our knowledge of 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 (more). We use biochemical, biophysical and genetic techniques to determine how topoisomerases carry out the cellular roles and how drugs block their function. We also study DNA structure and have utilized the topoisomerases to create new gene therapy vectors.
Through our understanding of DNA topoisomerases and DNA structure (more), we have created a tiny, non-viral DNA vector, called “Minivector DNA” for use in gene therapy. Minivector DNA transfects even cell types that are difficult to transfect, such as cells that grow in suspension. Minivectors survive human serum and regulate gene expression. Currently, we are exploring using Minivectors to regulate gene expression in animal models for human diseases with the hope to move the work to clinical trials.
- Fogg JM, Randall GL, Pettitt BM, Sumners de WL, Harris SA and Zechiedrich L. Bullied no more: when and how DNA shoves proteins around. Q Rev Biophys, 45(3):257-99 (2012). PubMed
- Catanese DJ Jr, Fogg JM, Schrock DE II, Gilbert BE and Zechiedrich L. Supercoiled Minivectors resist shear forces associated with gene therapy delivery. Gene Ther, 19:94-100 (2012). PubMed
- Swick MC, Morgan-Linnell SK, Carlson KM and Zechiedrich L. Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichi coli clinical isolates as a function of fluoroquinolone and multidrug resistance. Antimicrob Agents Chemother, 55:921-924 (2011). PubMed
- Zhao N, Fogg JM, Zechiedrich L and Zu Y. Transfection of shRNA-encoding Minivector DNA of a few hundred base pairs to regulate gene expression in lymphoma cells. Gene Ther, 18:220-224 (2011). PubMed
- Zechiedrich L and Osheroff N. Topoisomerase IB-DNA interactions: X marks the spot. Structure, 18(6):661-3 (2010). PubMed
- Liu Z, Zechiedrich L and Chan HS. Action at hooked or twisted DNA juxtapositions rationalizes unlinking preference of type-2 topoisomerases. J Mol Biol, 400:963-982 (2010). PubMed
- Randall GL, Zechiedrich L and Pettitt BM. In the absence of writhe, DNA relieves torsional stress with localized, sequence-dependent structural failure to preserve B-form. Nucleic Acids Res, 37(16):5568-77 (2009). PubMed
For more publications, see listing on PubMed.
Department: Molecular Virology & Microbiology and Biochemistry & Molecular Biology
Address: Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030 USA
Phone: 713-798-5126, 5127, 5148, or 6248